Carboxamide, Sulfonamide and Amine Compounds and Methods for Using The Same

ABSTRACT

Disclosed are carboxamide, sulfonamide and amine compounds, as well as pharmaceutical compositions and methods of use. One embodiment is a compound having the structure 
     
       
         
         
             
             
         
       
     
     in which R 1 , R 2 , R 4 , D, E, J, T, p, q and x are as described herein. In certain embodiments, a compound disclosed herein activates the AMPK pathway, and can be used to treat metabolism-related disorders and conditions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/334,201, filed Dec. 12, 2008, which claims the benefit of the earlierfiling dates of U.S. Provisional Patent Applications Ser. No.61/013,114, filed Dec. 12, 2007; Ser. No. 61/013,124, filed Dec. 12,2007; Ser. No. 61/016,402, filed Dec. 21, 2007; Ser. No. 61/016,405,filed Dec. 21, 2007; Ser. No. 61/016,406, filed Dec. 21, 2007; and Ser.No. 61/078,209, filed Jul. 3, 2008. Each application referenced in thisparagraph is hereby incorporated herein by reference in its entirety.

BACKGROUND

1. Field

This disclosure relates generally to compounds, pharmaceuticalcompositions and methods of use of the compounds and compositionscontaining them. This disclosure relates more particularly to certaincarboxamide, sulfonamide and amine compounds and pharmaceuticalcompositions thereof, and to methods of treating and preventingmetabolic disorders such as type II diabetes, atherosclerosis andcardiovascular disease using certain carboxamide, sulfonamide and aminecompounds.

2. Technical Background

Adiponectin is a protein hormone exclusively expressed in and secretedfrom adipose tissue and is the most abundant adipose-specific protein.Adiponectin has been implicated in the modulation of glucose and lipidmetabolism in insulin-sensitive tissues. Decreased circulatingadiponectin levels have been demonstrated in some insulin-resistantstates, such as obesity and type 2 diabetes mellitus and also inpatients with coronary artery disease, atherosclerosis and hypertension.Adiponectin levels are positively correlated with insulin sensitivity,HDL (high density lipoprotein) levels and insulin stimulated glucosedisposal and inversely correlated with adiposity and glucose, insulinand triglyceride levels. Thiazolidinedione drugs, which enhance insulinsensitivity through activation of the peroxisome proliferator-activatedreceptor-γ, increase endogenous adiponectin production in humans.

Adiponectin binds its receptors in liver and skeletal muscle and therebyactivates the 5′-AMP-activated protein kinase (AMPK) pathway.Adiponectin receptors 1 and 2 are membrane-bound proteins found inskeletal muscle and liver tissue. Being a multi-substrate enzyme, AMPKregulates a variety of metabolic processes, such as glucose transport,glycolysis and lipid metabolism. It acts as a sensor of cellular energyhomeostasis and is activated in response to certain hormones and musclecontraction as well as to intracellular metabolic stress signals such asexercise, ischemia, hypoxia and nutrient deprivation. Once activated,AMPK switches on catabolic pathways (such as fatty acid oxidation andglycolysis) and switches off ATP-consuming pathways (such aslipogenesis). Adiponectin improves insulin sensitivity by directlystimulating glucose uptake in adipocytes and muscle and by increasingfatty acid oxidation in liver and muscle, resulting in reducedcirculating fatty acid levels and reduced intracellular triglyceridecontents. Moreover, adiponectin decreases glycogen concentration byreducing the activity of glycogen synthase. Adiponectin also plays aprotective role against inflammation and atherosclerosis. It suppressesthe expression of adhesion molecules in vascular endothelial cells andcytokine production from macrophages, thus inhibiting the inflammatoryprocesses that occur during the early phases of atherosclerosis. What isneeded are compounds, pharmaceutical compositions and methods of usingthem to treat disease states associated with circulating adiponectinlevels, such as type II diabetes, atherosclerosis and cardiovasculardisease.

SUMMARY

Disclosed herein are compounds having structural formula (I)

and pharmaceutically acceptable salts, prodrugs and N-oxides thereof(and solvates and hydrates thereof), wherein

-   -   “B” represents -(aryl or heteroaryl)- substituted by w R³ and k        R¹⁴;    -   the dotted line denoted by “b” is absent, a single bond or a        double bond;    -   the dotted line denoted by “a” is a bond or absent, provided        that if the dotted line denoted by “b” is a double bond, then        the dotted line denoted by “a” is absent;    -   D is a carbon or N when the dotted line denoted by “a” is        absent, and a carbon when the dotted line denoted by “a” is a        bond;    -   J is —O—, —N(R³⁸)—, —CH₂—, —CH(R²⁶)— or —C(R²⁶)₂—;    -   E is —C(O)—, —S(O)₂— or a single bond;    -   R¹ is H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) or —C(O)O—(C₁-C₄        alkyl);    -   R² is -Hca, -Cak-N(R⁹)-G-R²² or —(C₂-C₈ alkyl)-N(R⁹)—R²⁴ in        which one or two carbons of the (C₂-C₈ alkyl) are optionally        replaced by —O—, —S— or —N(R⁹)— and R²⁴ is —R²³, -G-R²³ or        —C(O)O—(C₁-C₆ alkyl), provided that two consecutive carbons of        the (C₂-C₈ alkyl) are not replaced by —O—;    -   each R³ is substituted on a benzo, pyrido or pyrazino carbon of        the ring system denoted by “B” and is independently selected        from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar,        —(C₀-C₆ alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca,        —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰,        —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen,        —NO₂ and —CN;    -   w is 0, 1, 2 or 3;    -   each R¹⁴ is substituted on a non-benzo, non pyrido, non-pyrazino        carbon of the ring system denoted by “B”, and is independently        selected from —(C₁-C₆ alkyl), —(C₁-C₆ halooalkyl), —(C₀-C₆        alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆        alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆        alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰,        -halogen, —NO₂ and —CN;    -   k is 0, 1 or 2;    -   each R⁴ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆        haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆        alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆        alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰,        —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, and two R⁴ on        the same carbon optionally combine to form oxo;    -   x is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4;    -   q is 0, 1, 2, 3 or 4;    -   the sum of p and q is 1, 2, 3 or 4;    -   T is —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆        alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰        or

-   -   in which        -   Q is —S(O)₂—, L or (C₀-C₃ alkyl)-, in which each carbon of            the —(C₀-C₃ alkyl)- is optionally and independently            substituted with one or two R¹⁶;        -   the ring system denoted by “A” is heteroaryl, aryl,            cycloalkyl or heterocycloalkyl;        -   each R⁵ is independently selected from —(C₁-C₆ alkyl),            —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het,            —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷,            —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆            alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂            and —CN; and        -   y is 0, 1, 2, 3 or 4;    -   in which        -   each L is independently selected from —NR⁹C(O)O—,            —OC(O)NR⁹—, —NR⁹C(O)—NR⁹—, —NR⁹C(O)S—, —SC(O)NR⁹—,            —NR⁹C(O)—, —C(O)—NR⁹—, —NR⁹C(S)O—, —OC(S)NR⁹—,            —NR⁹C(S)—NR⁹—, —NR⁹C(S)S—, —SC(S)NR⁹—, —NR⁹C(S)—, —C(S)NR⁹—,            —SC(O)NR⁹—, —NR⁹C(S)—, —S(O)₀₋₂—, —C(O)O, —OC(O)—, —C(S)O—,            —OC(S)—, —C(O)S—, —SC(O)—, —C(S)S—, —SC(S)—, —OC(O)O—,            —SC(O)O—, —OC(O)S—, —SC(S)O—, —OC(S)S—, —NR⁹C(NR²)NR⁹—,            —NR⁹SO₂—, —SO₂NR⁹— and —NR⁹SO₂NR⁹—,        -   each R⁶, R⁷, R⁸ and R¹⁰ is independently selected from H,            —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar,            —(C₀-C₆ alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca,            —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹—(C₀-C₆            alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆            alkyl)-C(O)—(C₀-C₆ alkyl) and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆            alkyl),        -   each R⁹ is independently selected from —H, —(C₁-C₄ alkyl),            —C(O)—(C₁-C₄ alkyl) and —C(O)O—(C₁-C₄ alkyl),        -   each G is independently-S(O)₂—, L or —(C₀-C₃ alkyl)-, in            which each carbon of the —(C₀-C₃ alkyl)- is optionally and            independently substituted with one or two R¹⁶,        -   each R¹⁶ is independently selected from —(C₁-C₆ alkyl),            —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het,            —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷,            —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆            alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂            and —CN, and optionally two of R¹⁶ on the same carbon            combine to form oxo,        -   each R²⁶ is independently selected from —(C₁-C₆ alkyl),            —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het,            —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷,            —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆            alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂            and —CN, and optionally two of R²⁶ on the same carbon            combine to form oxo,        -   each R³⁸ is independently selected from —H, —(C₁-C₄ alkyl),            —C(O)—(C₁-C₄ alkyl) and —C(O)O—(C₁-C₄ alkyl),        -   each R²² and R²³ is independently Ar or Het,        -   each Ar is an optionally substituted aryl,        -   each Het is an optionally substituted heteroaryl,        -   each Cak is an optionally substituted cycloalkyl,        -   each Hca is an optionally substituted heterocycloalkyl, and        -   each alkyl is optionally substituted.

Also disclosed herein are pharmaceutical compositions. Examples of suchcompositions include those having at least one pharmaceuticallyacceptable carrier, diluent or excipient; and a compound,pharmaceutically acceptable salt, prodrug or N-oxide (or solvate orhydrate) described above.

Another aspect of the present disclosure includes methods for modulatingmetabolism in subjects. Accordingly, also disclosed are methods fortreating metabolic disorders using the presently disclosed compounds andpharmaceutical compositions.

DETAILED DESCRIPTION

One aspect of the disclosure provides compounds having structuralformula (I):

and pharmaceutically acceptable salts, prodrugs and N-oxides thereof(and solvates and hydrates thereof), in which

-   -   “B” represents -(aryl or heteroaryl)- substituted by w R³ and k        R¹⁴;    -   the dotted line denoted by “b” is absent, a single bond or a        double bond;    -   the dotted line denoted by “a” is a bond or absent, provided        that if the dotted line denoted by “b” is a double bond, then        the dotted line denoted by “a” is absent;    -   D is a carbon or N when the dotted line denoted by “a” is        absent, and a carbon when the dotted line denoted by “a” is a        bond;    -   J is —O—, —N(R³⁸)—, —CH₂—, —CH(R²⁶)— or —C(R²⁶)₂—;    -   E is —C(O)—, —S(O)₂— or a single bond, provided that when “B” is        phenyl, J is —O— and D is a carbon, E is not —C(O)—;    -   R¹ is H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) or —C(O)O—(C₁-C₄        alkyl);    -   R² is -Hca, -Cak-N(R⁹)-G-R²² or —(C₂-C₈ alkyl)-N(R⁹)—R²⁴ in        which one or two carbons of the (C₂-C₈ alkyl) are optionally        replaced by —O—, —S— or —N(R⁹)— and R²⁴ is —R²³, -G-R²³, or        —C(O)O—(C₁-C₆ alkyl), provided that two consecutive carbons of        the (C₂-C₈ alkyl) are not replaced by —O—;    -   each R³ is substituted on a benzo, pyrido or pyrazino carbon of        the ring system denoted by “B” and is independently selected        from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar,        —(C₀-C₆ alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca,        —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰,        —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen,        —NO₂ and —CN;    -   w is 0, 1, 2 or 3;    -   each R¹⁴ is substituted on a non-benzo, non-pyrido, non-pyrazino        carbon of the ring system denoted by “B”, and is independently        selected from —(C₁-C₆ alkyl), —(C₁-C₆ halooalkyl), —(C₀-C₆        alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆        alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆        alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰,        -halogen, —NO₂ and —CN;    -   k is 0, 1 or 2;    -   each R⁴ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆        haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆        alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆        alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰,        —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, and two R⁴ on        the same carbon optionally combine to form oxo;    -   x is 0, 1, 2, 3 or 4;    -   p is 0, 1, 2, 3 or 4;    -   q is 0, 1, 2, 3 or 4;    -   the sum of p and q is 1, 2, 3 or 4;    -   T is —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆        alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰        or

-   -   in which        -   Q is —S(O)₂—, L or —(C₀-C₃ alkyl)-, in which each carbon of            the —(C₀-C₃ alkyl)- is optionally and independently            substituted with one or two R¹⁶;        -   the ring system denoted by “A” is heteroaryl, aryl,            cycloalkyl or heterocycloalkyl;        -   each R⁵ is independently selected from —(C₁-C₆ alkyl),            —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het,            —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷,            —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆            alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, —(C₀-C₆            alkyl)-C(O)R¹⁰, -halogen, —NO₂ and —CN; and        -   y is 0, 1, 2, 3 or 4;    -   in which        -   each L is independently selected from —NR⁹C(O)O—,            —OC(O)NR⁹—, —NR⁹C(O)—NR⁹—, —NR⁹C(O)S—, —SC(O)NR⁹—,            —NR⁹C(O)—, —C(O)—NR⁹—, —NR⁹C(S)O—, —OC(S)NR⁹—,            —NR⁹C(S)—NR⁹—, —NR⁹C(S)S—, —SC(S)NR⁹—, —NR⁹C(S)—, —C(S)NR⁹—,            —SC(O)NR⁹—, —NR⁹C(S)—, —S(O)₀₋₂—, —C(O)O, —OC(O)—, —C(S)O—,            —OC(S)—, —C(O)S—, —SC(O)—, —C(S)S—, —SC(S)—, —OC(O)O—,            —SC(O)O—, —OC(O)S—, —SC(S)O—, —OC(S)S—, —NR⁹C(NR²)NR⁹—,            —NR⁹SO₂—, —SO₂NR⁹— and —NR⁹SO₂NR⁹—,        -   each R⁶, R⁷, R⁸ and R¹⁰ is independently selected from H,            —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar,            —(C₀-C₆ alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca,            —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹—(C₀-C₆            alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆            alkyl)-C(O)—(C₀-C₆ alkyl) and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆            alkyl),        -   each R⁹ is independently selected from —H, —(C₁-C₄ alkyl),            —C(O)—(C₁-C₄ alkyl) and —C(O)O—(C₁-C₄ alkyl),        -   each G is independently —S(O)₂—, L or —(C₀-C₃ alkyl)-, in            which each carbon of the —(C₀-C₃ alkyl)- is optionally and            independently substituted with one or two R¹⁶, or        -   each R¹⁶ is independently selected from —(C₁-C₆ alkyl),            —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het,            —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷,            —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆            alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂            and —CN, and optionally two of R¹⁶ on the same carbon            combine to form oxo,        -   each R²⁶ is independently selected from —(C₁-C₆ alkyl),            —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het,            —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷,            —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆            alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂            and —CN, and optionally two of R²⁶ on the same carbon            combine to form oxo,        -   each R³⁸ is independently selected from —H, —(C₁-C₄ alkyl),            —C(O)—(C₁-C₄ alkyl) and —C(O)O—(C₁-C₄ alkyl),        -   each R²² and R²³ is independently Ar or Het,        -   each Ar is an optionally substituted aryl,        -   each Het is an optionally substituted heteroaryl,        -   each Cak is an optionally substituted cycloalkyl,        -   each Hca is an optionally substituted heterocycloalkyl, and        -   each alkyl is optionally substituted.

In certain embodiments of the presently disclosed compounds ofstructural formula (I), the compound is not

-   5-methyl-N,2-bis(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide    or-   5-methyl-2-(tetrahydro-2H-pyran-4-yl)-N-(tetrahydrothiophen-2-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide    S,S-dioxide.

In certain embodiments of the presently disclosed compounds ofstructural formula (I), J is —O— or —N(R³⁸)—. In certain suchembodiments, D can be, for example, a carbon (for example, it is CH or Csubstituted with one of the x R⁴ groups when the bond denoted by “a” isabsent, or C when the bond denoted by “a” is present). In otherembodiments of the presently disclosed compounds of structural formula(I), J is —CH₂—, —CH(R²⁶)— or —C(R²⁶)₂—, for example, —CH₂—. In certainsuch embodiments, D can be, for example, N.

In certain embodiments of the presently disclosed compounds ofstructural formula (I), R³⁸ is —H. In other embodiments, R³⁸ is —(C₁-C₄alkyl), for example methyl, ethyl or propyl. In other embodiments, R³⁸is —C(O)—(C₁-C₄ alkyl), for example acetyl. In other embodiments, R³⁸ is—C(O)—O—(C₁-C₄ alkyl)-, for example —C(O)—O-t-butyl. In certainembodiments, no alkyl of R³⁸ is substituted with an aryl-, heteroaryl-,cycloalkyl- or heterocycloalkyl-containing group.

In certain embodiments of the presently disclosed compounds ofstructural formula (I), each R²⁶ is independently selected from —(C₁-C₆alkyl), —(C₁-C₆ haloalkyl) (e.g., difluoromethyl, trifluoromethyl andthe like), —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰,-halogen, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰ is independentlyselected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl), and —(C₀-C₆alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. For example, in one embodiment, eachR²⁶ is independently selected from —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl),—(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, inwhich each R⁷, R⁸ and R¹⁰ is independently selected from H, —(C₁-C₂alkyl), —(C₁-C₂ haloalkyl), —(C₀-C₂ alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂ alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), andin which no alkyl or haloalkyl is substituted with an aryl-,heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. Incertain embodiments, each R²⁶ is methyl, ethyl, propyl, or two R²⁶ cometogether to form oxo.

In certain embodiments of the presently disclosed compounds ofstructural formula (I) as described above, the dotted line denoted by“b” is absent. In other embodiments, the dotted line denoted by “b” is asingle bond; in one such embodiment, the dotted line denoted by “a” is abond (thereby forming a double bond between D and the adjacent carbon).

In certain embodiments of the presently disclosed compounds ofstructural formula (I), E is —C(O)—. In other embodiments, E is —S(O)₂—.

In certain embodiments of the presently disclosed compounds ofstructural formula (I), “B” represents

the dotted line denoted by “b” is a single bond, the dotted line denotedby “a” is a bond, k is 0, J is —N(R³⁸)— and D is a carbon. In one suchembodiment, E is —C(O)—.

In other embodiments of the presently disclosed compounds of structuralformula (I),

“B” represents the dotted line denoted by “b” is absent, the dotted linedenoted by “a” is absent, k is 0, J is —N(R³⁸)— and D is a carbon. Inone such embodiment, E is —C(O)—.

In other embodiments of the presently disclosed compounds of structuralformula (I), “B” represents

in which X¹ and X² are independently a carbon (for example, CH or Csubstituted with one of the w R³ groups) or N, and k is 0. In one suchembodiment, E is —C(O)—. In certain embodiments, one of X¹ and X² is Nand the other is a carbon. In other embodiments, both X¹ and X² are acarbon. Floating bonds indicate attachment on any carbon of the ringsystem. In some embodiments, for example, the J moiety is on one ring ofthe ring system, and the E moiety is on the other ring of thenaphthalene, and any R³ groups can be on either ring of the fused ringsystem.

In other embodiments of the presently disclosed compounds of structuralformula (I), “B” represents

in which R³⁹ is H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) or —C(O)O—(C₁-C₄alkyl). In certain such embodiments, E is —C(O)—. In certainembodiments, one R¹⁴ can be substituted on the pyrrolo carbon. In onesuch embodiment, R¹⁴ is selected from (C₁-C₆ alkyl), —(C₁-C₆ haloalkyl)(e.g., difluoromethyl, trifluoromethyl and the like), —(C₀-C₆alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, inwhich each R⁷, R⁸ and R¹⁰ is independently selected from H, —(C₁-C₆alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆alkyl)-C(O)—(C₀-C₆ alkyl), and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), andin which no alkyl or haloalkyl is substituted with an aryl-,heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. Forexample, in one embodiment, R¹⁴ is selected from —(C₁-C₃ alkyl), —(C₁-C₃haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰,-halogen, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰ is independentlyselected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl), —(C₀-C₂alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. R¹⁴ can be, for example, halo (e.g.,—Cl or —F), cyano, unsubstituted —(C₁-C₄ alkyl) (e.g., methyl or ethyl),or unsubstituted —(C₁-C₄ haloakyl) (e.g., difluoromethyl,trifluoromethyl and the like). In certain embodiments, R¹⁴ is H ormethyl; in others, R¹⁴ is halo (e.g., Cl). In other embodiments, no R¹⁴is substituted on the pyrrolo carbon.

In certain embodiments of the presently disclosed compounds ofstructural formula (I), T is

In such embodiments, Q is —S(O)₂—, L or —(C₀-C₃ alkyl)- in which eachcarbon of the (C₀-C₃ alkyl) is optionally and independently substitutedwith one or two R¹⁶, in which each R¹⁶ is independently selected from—(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷,—(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰,—(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, and optionally two ofR¹⁶ on the same carbon combine to form oxo. In certain embodiments, eachR¹⁶ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl)(e.g., difluoromethyl, trifluoromethyl and the like), —(C₀-C₆alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, andtwo R¹⁶ on the same carbon optionally combine to form an oxo, in whicheach R⁷, R⁸ and R¹⁰ is independently selected from H, —(C₁-C₆ alkyl),—(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆alkyl)-C(O)—(C₀-C₆ alkyl), and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), andin which no alkyl or haloalkyl is substituted with an aryl-,heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. Forexample, in particular compounds, each R¹⁶ is —(C₁-C₃ alkyl), —(C₁-C₃haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰,-halogen, —NO₂ and —CN, and two R¹⁶ on the same carbon optionallycombine to form an oxo, in which each R⁷, R⁸ and R¹⁰ is independentlyselected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl), —(C₀-C₂alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. In certain embodiments, Q has at mostone R¹⁶ or an oxo substituted thereon. Q can be, for example, anunsubstituted —(C₀-C₃ alkyl)-. In other embodiments, Q is a (C₁-C₃alkyl) having as its only substitution a single oxo group. For example,in certain embodiments, Q is —CH₂—; a single bond; —S(O)₂—; —C(O)—; or—CH(CH₃)—.

In certain embodiments of the compounds of structural formula (I), the

moiety is

for example, p-(trifluoromethyl)phenyl. In other embodiments, the

moiety is

in one such embodiment, Q is a single bond.

The number of substituents on the ring system denoted by “A”, y, is 0,1, 2, 3 or 4. For example, in some embodiments of the presentlydisclosed compounds of structural formula (I), y is 0, 1, 2 or 3, suchas 1. In one embodiment, y is not zero and at least one R⁵ is halo,cyano, —(C₁-C₄ haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl),—O—(C₁-C₄ alkyl), —C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl),—C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), NO₂ or —C(O)—Hca wherein the Hcacontains a ring nitrogen atom through which it is bound to the —C(O)—,and wherein no alkyl, haloalkyl or heterocycloalkyl is substituted by anaryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group.

In certain embodiments of the presently disclosed compounds ofstructural formula (I), each R⁵ is independently selected from —(C₁-C₆alkyl), —(C₁-C₆ haloalkyl) (e.g., difluoromethyl, trifluoromethyl andthe like), —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰,-halogen, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰ is independentlyselected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl) (e.g.,difluoromethyl, trifluoromethyl and the like), —(C₀-C₆ alkyl)-L-(C₀-C₆alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl),—(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl) and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-,heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. Forexample, in one embodiment, each R⁵ is —(C₁-C₃ alkyl), —(C₁-C₃haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰,-halogen, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰ is independentlyselected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl), —(C₀-C₂alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group.

In one embodiment of the compounds of structural formula (I), y is 0.

In the presently disclosed compounds of structural formula (I), the ringsystem denoted by “A” is heteroaryl, aryl, cycloalkyl orheterocycloalkyl. For example, in one embodiment, the ring systemdenoted by “A” is an aryl or a heteroaryl. The ring system denoted by“A” can be, for example, a monocyclic aryl or heteroaryl. In oneembodiment, when the “A” ring system is aryl, Q is a —(C₀-C₃ alkyl)-optionally substituted with oxo, and optionally substituted with one ormore R¹⁶. For example, Q can be a —(C₁-C₃ alkyl)- having its onlysubstitution a single oxo, or an unsubstituted —(C₀-C₃ alkyl)-. Forexample, in certain embodiments, Q is —CH₂—; a single bond; —S(O)₂—;—C(O)—; or —CH(CH₃)—.

For example, in certain embodiments of the presently disclosed compoundsof structural formula (I), the ring system denoted by “A” is a phenyl.In one embodiment, y is 1 and R⁵ is attached to the phenyl in the paraposition relative to Q. In another embodiment, y is 1 and R⁵ is selectedfrom the group consisting of halo, cyano, —(C₁-C₄ haloalkyl), —O—(C₁-C₄haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl), —C(O)—(C₀-C₄ alkyl),—C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), NO₂ and—C(O)—Hca in which the Hca contains a ring nitrogen atom through whichit is bound to the —C(O)—, and in which no (C₀-C₄ alkyl) or (C₁-C₄alkyl) is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. R⁵ can be, for example, —Cl, —F,cyano, —C(O)CH₃, —C(O)OH, —C(O)NH₂, trifluoromethyl, difluoromethyl,difluoromethoxy or trifluoromethoxy. In another embodiment, the

moiety is a 3,4-dihalophenyl.

In another embodiment of the presently disclosed compounds of structuralformula (I), the ring system denoted by “A” is a heteroaryl. Forexample, in certain embodiments, the ring system denoted by “A” is apyridyl, a thienyl, or a furanyl. In one embodiment, when the “A” ringsystem is heteroaryl, Q is a —(C₀-C₃ alkyl)- optionally substituted withoxo, and optionally substituted with one or more R¹⁶. For example, Q canbe a —(C₁-C₃ alkyl)- having its only substitution a single oxo, or anunsubstituted —(C₀-C₃ alkyl)-. In certain embodiments, Q is —CH₂—; asingle bond; —S(O)₂—; —C(O)—; or —CH(CH₃)—.

In one embodiment of the presently disclosed compounds, the compound hasstructural formula (II):

in which the variables are defined as described above with reference tostructural formula (I). In certain embodiments, R³⁸ is not H. Forexample, R³⁸ can in one embodiment be methyl, ethyl or propyl. Inanother embodiment, R³⁸ can be acetyl. In other embodiments, R³⁸ is H.

In one embodiment of the presently disclosed compounds, the compound hasstructural formula (III):

in which the variables are defined as described above with reference tostructural formula (I). In certain embodiments, R³⁸ is not H. Forexample, R³⁸ can in one embodiment be methyl, ethyl or propyl. Inanother embodiment, R³⁸ can be acetyl. In other embodiments, R³⁸ is H.

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (IV):

in which k is 0, q is 1, 2, 3 or 4, J is —CH₂—, —CH(R²⁶)— or —C(R²⁶)₂—(e.g., —CH₂—), and all other variables are defined as described abovewith reference to structural formula (I).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (V):

in which k is 0, q is 1, 2, 3 or 4, J is —CH₂—, —CH(R²⁶)— or —C(R²⁶)₂—(e.g., —CH₂—), and all other variables are defined as described abovewith reference to structural formula (I).

In certain embodiments according to structural formulae (I)-(V), the sumof p and q is 2 or 3. For example, in one embodiment, the sum of p and qis 2 (e.g., p is 1 and q is 1). In another embodiment, the sum of p andq is 3 (e.g., p is 1 and q is 2).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (VI):

in which k is 0, n is 0, 1, 2 or 3, and all other variables are definedas described above with reference to structural formula (I).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (VII):

in which k is 0, n is 0, 1, 2 or 3, and all other variables are definedas described above with reference to structural formula (I).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (VIII):

in which k is 0, n is 0, 1, 2 or 3, one of X¹ and X² is N and the otheris a carbon, and all other variables are defined as described above withreference to structural formula (I). In one embodiment, for example, X¹is N and X² is a carbon. In another embodiment, X¹ is a carbon, and X²is N.

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (IX):

in which k is 0, n is 0, 1, 2 or 3, one of X¹ and X² is N and the otheris a carbon, and all other variables are defined as described above withreference to structural formula (I). In one embodiment, for example, X¹is N and X² is a carbon. In another embodiment, X¹ is a carbon, and X²is N.

In one embodiment of the presently disclosed compounds, the compound hasstructural formula (X):

in which n is 0, 1, 2 or 3 and all other variables are defined asdescribed above with reference to structural formula (I). In certainembodiments, one R¹⁴ is substituted on the pyrrolo carbon. In otherembodiments, no R¹⁴ is substituted on the pyrrolo carbon.

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (XI):

in which the variables are defined as described above with reference tostructural formula (I). In certain embodiments, one R¹⁴ is substitutedon the pyrrolo carbon. In other embodiments, no R¹⁴ is substituted onthe pyrrolo carbon.

In certain embodiments of the compounds disclosed with reference tostructural formulae (VI)-(XI), n is 1 or 2. For example, in oneembodiment, n is 2. In another embodiment, n is 1.

In one embodiment of the presently disclosed compounds, the compound hasthe structural formula (XII):

in which the variables are defined as described above with reference tostructural formulae (I) and (II).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (XIII):

in which the variables are defined as described above with reference tostructural formulae (I) and (III).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (XIV):

in which J is —CH₂—, —CH(R²⁶)— or —C(R²⁶)₂— (e.g., —CH₂—), and all othervariables are defined as described above with reference to structuralformulae (I) and (IV).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (XV):

in which J is —CH₂—, —CH(R²⁶)— or —C(R²⁶)₂— (e.g., —CH₂—), and all othervariables are defined as described above with reference to structuralformulae (I) and (V).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (XVI):

in which the variables are defined as described above with reference tostructural formulae (I) and (VI).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (XVII):

in which the variables are defined as described above with reference tostructural formulae (I) and (VII).

In one embodiment of the presently disclosed compounds, the compound hasstructural formula (XVIII):

in which one of X¹ and X² is N, and the other is a carbon; and the othervariables are defined as described above with reference to structuralformulae (I) and (VIII). In one embodiment, for example, X¹ is N and X²is a carbon. In another embodiment, X¹ is a carbon, and X² is N.

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (XIX):

in which one of X¹ and X² is N, and the other is a carbon; and the othervariables are defined as described above with reference to structuralformulae (I) and (IX). In one embodiment, for example, X¹ is N and X² isa carbon. In another embodiment, X¹ is a carbon, and X² is N.

In one embodiment of the presently disclosed compounds, the compound hasstructural formula (XX):

in which the variables are defined as described above with reference tostructural formulae (I) and (X). In certain embodiments, one R¹⁴ issubstituted on the pyrrolo carbon. In other embodiments, no R¹⁴ issubstituted on the pyrrolo carbon.

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (XXI):

in which the variables are defined as described above with reference tostructural formulae (I) and (XI). In certain embodiments, one R¹⁴ issubstituted on the pyrrolo carbon. In other embodiments, no R¹⁴ issubstituted on the pyrrolo carbon.

In certain embodiments of the presently disclosed compounds of any ofstructural formulae (I)-(XXI), R¹ is —H. In other embodiments, R¹ is(C₁-C₄ alkyl), for example methyl, ethyl, n-propyl or isopropyl.

In certain embodiments of the presently disclosed compounds of anystructural formulae (I)-(XXI), R² is -Hca. In certain embodiments, R² isan optionally-substituted monocyclic heterocycloalkyl. In anotherembodiment, R² is not an oxo-substituted heterocycloalkyl. In certainembodiments (e.g., when the compound has structural formula (II) or(III)), R² is not tetrahydro-2H-pyran-4-yl moiety or atetrahydrothiophene S,S-dioxide moiety.

In certain of the presently disclosed compounds of any structuralformulae (I)-(XXI), R² is -(optionally-substituted azetidinyl),-(optionally-substituted pyrrolidinyl), -(optionally-substitutedpiperidinyl), or -(optionally-substituted azepanyl). For example, R² canbe -(optionally substituted piperidinyl) or -(optionally substitutedpyrrolidinyl). In one embodiment, R² is -(optionally substitutedpiperidinyl). In another embodiment, R² is -(optionally substitutedpyrrolidinyl).

In certain particular embodiments of the presently disclosed compoundsof any of structural formulae (I)-(XXI), R² is -(optionally-substitutedazetidin-3-yl), -(optionally substituted piperidin-4-yl), -(optionallysubstituted pyrrolidin-3-yl) or -(optionally-substituted azepan-4-yl).For example, in one embodiment, R² is -(optionally substitutedpiperidin-4-yl). In another embodiment, R² is -(optionally substitutedpyrrolidin-3-yl).

In certain embodiments of the presently disclosed compounds of any ofstructural formulae (I)-(XXI), the azetidinyl, pyrrolidinyl, piperidinyland azepanyl R² moieties described above are substituted at their1-positions. For example, in one embodiment, R² is substituted at its1-position with —(C₀-C₃ alkyl)-Ar or —(C₀-C₃ alkyl)-Het, for example-(unsubstituted C₀-C₃ alkyl)-Ar or -(unsubstituted C₀-C₃ alkyl)-Het. Forexample, in one particular embodiment, the azetidinyl, pyrrolidinyl,piperidinyl or azepanyl R² moiety is substituted at its 1-position withan optionally substituted benzyl or an optionally substituted phenyl. Inanother embodiment, the azetidinyl, pyrrolidinyl, piperidinyl orazepanyl R² moiety is substituted at its 1-position with a benzylsubstituted with an electron withdrawing group; or with apyridinylmethyl optionally substituted with an electron withdrawinggroup. For example, the benzyl or pyridinylmethyl can be substitutedwith an electron withdrawing group selected from the group consisting ofhalo, cyano, —(C₁-C₄ fluoroalkyl), —O—(C₁-C₄ fluoroalkyl), —C(O)—(C₀-C₄alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl),—S(O)₂O—(C₀-C₄ alkyl), NO₂ and —C(O)—Hca in which the Hca includes anitrogen atom to which the —C(O)— is bound, in which no alkyl,fluoroalkyl or heterocycloalkyl is substituted with an aryl, heteroaryl,cycloalkyl or heterocycloalkyl-containing group. In other embodiments,the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R² moiety issubstituted at its 1-position with an unsubstituted benzyl or anunsubstituted phenyl.

In other embodiments of the compounds disclosed herein having any ofstructural formulae (I)-(XXI), the azetidinyl, pyrrolidinyl, piperidinylor azepanyl R² moiety is substituted at its 1-position with anoptionally substituted pyridinylmethyl, an optionally substitutedfuranylmethyl, an optionally substituted thienylmethyl, an optionallysubstituted oxazolylmethyl, or an optionally substitutedimidazolylmethyl. For example, the azetidinyl, pyrrolidinyl, piperidinylor azepanyl R² moiety can be substituted with an unsubstitutedpyridinylmethyl, an unsubstituted furanylmethyl, an unsubstitutedthienylmethyl, an unsubstituted oxazolylmethyl, or an unsubstitutedimidazolylmethyl. In other embodiments, the azetidinyl, pyrrolidinyl,piperidinyl or azepanyl R² moiety can be substituted with anpyridinylmethyl, furanylmethyl, thienylmethyl, oxazolylmethyl orimidazolylmethyl substituted with an electron withdrawing group asdescribed above.

In certain embodiments of the compounds disclosed herein having any ofstructural formulae (I)-(XXI), the azetidinyl, pyrrolidinyl, piperidinylor azepanyl R² moiety is substituted at its 1-position with -L-Ar or-L-Het, in which Ar and Het can be, for example, as described above withreference to —(C₀-C₃ alkyl)-Ar or —(C₀-C₃ alkyl)-Het. In one suchembodiment, L is —C(O)—NR⁹—, such as —C(O)—NH—.

In other embodiments of the presently disclosed compounds of any ofstructural formulae (I)-(XXI), the azetidinyl, pyrrolidinyl, piperidinylor azepanyl R² moiety is substituted at its 1-position with—C(O)—O(C₀-C₆ alkyl), —C(O)—Het, —C(O)—Ar, —S(O)₂-Het, —S(O)₂—Ar or—S(O)₂—O(C₀-C₆ alkyl), in which Ar and Het can be, for example, asdescribed above with reference to —(C₀-C₃ alkyl)-Ar or —(C₀-C₃alkyl)-Het. In one embodiment, the azetidinyl, pyrrolidinyl, piperidinylor azepanyl R² moiety is substituted at its 1-position with —C(O)—Het or—C(O)—Ar; in another embodiment, it is substituted at its 1-positionwith —S(O)₂-Het or —S(O)₂—Ar. For example, in certain embodiments, theazetidinyl, pyrrolidinyl, piperidinyl or azepanyl R² moiety issubstituted at its 1-position with an optionally-substituted benzoyl(e.g., substituted with an electron withdrawing group as describedabove); or with an optionally-substituted nicotinyl, isonicotinyl orpicolinyl (e.g., optionally substituted with an electron withdrawinggroup as described above). In other embodiments, the azetidinyl,pyrrolidinyl, piperidinyl or azepanyl R² moiety is substituted at its1-position with an unsubstituted benzoyl; or an unsubstitutednicotinoyl, isonicotinoyl or picolinoyl.

In certain embodiments of the compounds of any of structural formulae(I)-(XXI), R² is -Cak-N(R⁹)-G-R²², as described above. For example, inone embodiment of the disclosed compounds, R² has the structure

in which c is 0, 1, 2, 3 or 4, and each R²¹ is independently selectedfrom —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar, (C₀-C₆alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷,—(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰,—(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, and two R²¹ on thesame carbon optionally combine to form oxo. In certain embodiments ofthe presently disclosed compounds, each R²¹ is independently selectedfrom —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl) (e.g., difluoromethyl,trifluoromethyl and the like), —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN and two R²¹ on the same carbonoptionally combine to form oxo, in which each R⁷, R⁸ and R¹⁰ isindependently selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl),—(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl) and —(C₀-C₆alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. For example, in one embodiment, eachR²¹ is —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN and two R²¹ on the same carbonoptionally combine to form oxo, in which each R⁷, R⁸ and R¹⁰ isindependently selected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl),—(C₀-C₂ alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. In certain embodiments, c is 1 or 2.In other embodiments, c is 0. In certain embodiments, R⁹ is H. Incertain embodiments, G is a single bond. In certain embodiments of thepresently disclosed compounds, each R²² is not substituted with anaryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. Incertain embodiments of the presently disclosed compounds, each R²³ isnot substituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group.

In one embodiment of compounds of any of structural formulae (I)-(XXI),R² has the structure

In certain embodiments of the compounds of any of structural formulae(I)-(XXI), R² is —(C₂-C₈ alkyl)-N(R⁹)—R²⁴ in which one or two carbons ofthe (C₂-C₈ alkyl) are optionally replaced by —O— or —N(R⁹)— and R²⁴ is—R²³, -GR²³ or —C(O)O—(C₁-C₆ alkyl). In certain embodiments, the (C₂-C₈alkyl) is unsubstituted and no carbon is replaced by —O— or —N(R⁹)—. Forexample, in one embodiment, R² is —CH₂—CH₂—CH₂—N(R⁹)—R²⁴ or—CH₂—CH₂—CH₂—CH₂—N(R⁹)—R²⁴. In other embodiments, the (C₂-C₈ alkyl) issubstituted and/or one or two carbons are replaced by —O— or —N(R⁹)—.For example, in one embodiment, R² is —CH₂—CH₂—O—CH₂—CH₂—N(R⁹)—R²⁴;—CH₂—CH(CH₃)—N(R⁹)—R²⁴; or —CH₂—CH₂—O—CH₂—C(O)—N(R⁹)—R²⁴. In certainembodiments, R⁹ is H. In certain embodiments, R²⁴ is Ar or Het. Incertain embodiments, R²⁴ is not substituted with an aryl-, heteroaryl-,cycloalkyl- or heterocycloalkyl-containing group. In certainembodiments, the (C₂-C₈ alkyl) is a (C₂-C₅ alkyl).

In the compounds of any of structural formulae (I)-(XXI), the number ofsubstituents on benzo, pyrido or pyrazino carbons of the ring systemrepresented by “B”, w, is 0, 1, 2 or 3. For example, in one embodiment,w is 0, 1 or 2. In another embodiment, such as when the ring systemrepresented by “B” does not include a benzo, pyrido or pyrazino moeity,w is 0. In other embodiments, w is at least 1, and at least one R³ isselected from the group consisting of halo, cyano, —(C₁-C₄ fluoroalkyl),—O—(C₁-C₄ fluoroalkyl), —C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl),—C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), —S(O)₂O—(C₀-C₄ alkyl), NO₂ and—C(O)—Hca in which the Hca includes a nitrogen atom to which the —C(O)—is bound, in which no alkyl, fluoroalkyl or heterocycloalkyl issubstituted with an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. For example, in certain embodiments,at least one R³ is halo (e.g., chloro) or —(C₁-C₄ alkyl) (e.g., methyl,ethyl or propyl). In certain embodiments, an R³ is substituted on the“B” ring system at a benzo, pyrido or pyrazino ring position in the metaposition relative to the J moiety.

In certain embodiments of the compounds of any of structural formulae(I)-(XXI),

each R³ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C₀-C₆alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, inwhich each R⁷, R⁸ and R¹⁰ is independently selected from H, —(C₁-C₆alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆alkyl)-C(O)—(C₀-C₆ alkyl), and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), andin which no alkyl or haloalkyl is substituted with an aryl-,heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. Forexample, in one embodiment, each R³ is —(C₁-C₃ alkyl), —(C₁-C₃haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰,-halogen, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰ is independentlyselected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl), —(C₀-C₂alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. For example, in certain embodiments,each R³ is halo (e.g., chloro) or —(C₁-C₄ alkyl) (e.g., methyl, ethyl orpropyl).

In certain embodiments of the compounds of any of structural formulae(I)-(XXI),

w is at least one, and at least one R³ is —NR⁸R⁹. For example, in oneembodiment, w is 1. In certain such embodiments, R³ is substituted onthe “B” ring system at a benzo, pyrido or pyrazino ring position in themeta position relative to the J moiety.

In other embodiments of the compounds of any of structural formulae(I)-(XXI), w is at least one, and at least one R³ is —(C₀-C₃alkyl)-Y¹—(C₁-C₃ alkyl)-Y²—(C₀-C₃ alkyl), in which each of Y¹ and Y² isindependently L, —O—, —S— or —NR⁹—. For example, in one embodiment, wis 1. In certain such embodiments, R³ is substituted on the “B” ringsystem at a benzo, pyrido or pyrazino ring position in the meta positionrelative to the J moiety. In one particular embodiment, R³ is—CH₂—N(CH₃)—CH₂—C(O)—OCH₃.

In the compounds of structural formula (I), the number of substituentson non-benzo, non-pyrido, non-pyrazino carbons, k, is 0, 1 or 2. Forexample, in one embodiment, k is 1. In other embodiments, such as whenthe ring system represented by “B” contains only benzo, pyridino and/orpiperazino carbons, k is 0. In certain embodiments of the compounds ofstructural formula (I), each R¹⁴ is independently selected from —(C₁-C₆alkyl), —(C₁-C₆ haloalkyl) (e.g., difluoromethyl, trifluoromethyl andthe like), —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰,-halogen, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰ is independentlyselected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl), and —(C₀-C₆alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. For example, in one embodiment, eachR¹⁴ is independently selected from —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl),—(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, inwhich each R⁷, R⁸ and R¹⁰ is independently selected from H, —(C₁-C₂alkyl), —(C₁-C₂ haloalkyl), —(C₀-C₂ alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂ alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), andin which no alkyl or haloalkyl is substituted with an aryl-,heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. Each R¹⁴can be, for example, halo (e.g., —Cl or —F), cyano unsubstituted —(C₁-C₄alkyl) (e.g., methyl or ethyl) or unsubstituted —(C₁-C₄ haloakyl) (e.g.,difluoromethyl, trifluoromethyl and the like).

In the presently disclosed compounds of any of structural formulae(I)-(XXI), the number of substituents on the azacycloalkyl ring, x, is0, 1, 2, 3 or 4. In one embodiment, x is 0, 1, 2 or 3. For example, xcan be 0, or can be 1 or 2.

In certain embodiments of the presently disclosed compounds of any ofstructural formula (I)-(XXI), two R⁴ groups combine to form an oxo. Theoxo can be bound, for example, at the position alpha to the nitrogen ofthe azacycloalkyl ring. In other embodiments, no two R⁴ groups combineto form an oxo.

In certain embodiments of the presently disclosed compounds of any ofstructural formulae (I)-(XXI), when x is 4, not all four R⁴ groups are(C₁-C₆ alkyl).

In certain embodiments of the presently disclosed compounds of any ofstructural formulae (I)-(XXI), each R⁴ is independently selected from—(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl) (e.g., difluoromethyl,trifluoromethyl and the like), —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰is independently selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl),—(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl) and —(C₀-C₆alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. For example, in one embodiment, eachR⁴ is —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰is independently selected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl),—(C₀-C₂ alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group.

In certain embodiments, the presently disclosed compounds have thestructural formula (XXII):

in which Q and G are each independently a bond, —CH₂—, —C(H)(R¹⁶)—,—C(R¹⁶)₂—, L (e.g., —C(O)—NR⁹— or —NR⁹—C(O)—) or —S(O)₂—; v is 0, 1, 2,3 or 4; each R¹⁵ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆ alkyl)-Cak,—(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰,-halogen, —NO₂ and —CN, and two R¹⁵ on the same carbon optionallycombine to form oxo; R¹⁷ is Het or Ar, and all other variables aredefined as described above with reference to any of structural formula(I)-(XXI). In one embodiment, Q is a single bond. In another embodiment,Q is —CH₂—. In other embodiments, Q is —C(O)— or —S(O)₂—. In certainembodiments, G is —CH₂—. In other embodiments, G is —C(O)— or —S(O)₂—.In other embodiments, G is —CH(CH₃)—. In other embodiments, G is—C(O)—NH—. The above-recited Q and G moieties can be combined in anypossible combination. For example, in one embodiment, Q is a single bondand G is —CH₂— or —C(O)—. As described above, in certain embodiments,the ring system denoted by “A” is aryl or heteroaryl. In one embodiment,the ring system denoted by “A” is substituted with one or moreelectron-withdrawing groups as described above. In another embodiment,R¹⁷ is substituted with one or more electron-withdrawing groups asdescribed above. In certain embodiments, the ring system denoted by “A”,R¹⁷ or both are not substituted with an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In certain embodiments, theazacycloalkyl to which -G-R¹⁷ is bound is a piperidinyl; in otherembodiments, it is a pyrrolidinyl.

In the presently disclosed compounds of structural formula (XXII), v is0, 1, 2, 3 or 4. In one embodiment, v is 0, 1, 2 or 3. For example, vcan be 0, or can be 1 or 2.

In certain embodiments of the presently disclosed compounds ofstructural formula (XXII), two R¹⁵ groups combine to form an oxo. Theoxo can be bound, for example, at the position alpha relative to thenitrogen of the azacycloalkyl ring. In other embodiments, no two R¹⁵groups combine to form an oxo.

In certain embodiments of the presently disclosed compounds ofstructural formula (XXII), when v is 4, not all four R¹⁵ moieties are(C₁-C₆ alkyl).

In certain embodiments of the presently disclosed compounds ofstructural formula (XXII), each R¹⁵ is independently selected from—(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl) (e.g., difluoromethyl,trifluoromethyl and the like), —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁹, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN and two R¹⁵ on the same carbonoptionally combine to form oxo, in which each R⁷, R⁸ and R¹⁰ isindependently selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl),—(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl) and —(C₀-C₆alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. For example, in one embodiment, eachR¹⁵ is —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁹, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN and two R¹⁵ on the same carbonoptionally combine to form oxo, in which each R⁷, R⁸ and R¹⁰ isindependently selected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl),—(C₀-C₂ alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. In some embodiments, one R¹⁵ is—C(O)NR⁹R⁷, which can be bound, for example, at a position alpharelative to the piperidine nitrogen, or at the position linked to the—N(R¹)—.

In certain embodiments of the presently disclosed compounds ofstructural formula (XXII), R¹⁷ is an unsubstituted aryl or heteroaryl.In other embodiments, the R¹⁷ Ar or Het is substituted with 1, 2 or 3substituents independently selected from —(C₁-C₆ alkyl), —(C₁-C₆haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like), —(C₀-C₆alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, inwhich each R⁷, R⁸ and R¹⁰ is independently selected from H, —(C₁-C₆alkyl), (C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆alkyl)-C(O)—(C₀-C₆ alkyl) and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), andin which no alkyl or haloalkyl is substituted with an aryl-,heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. Forexample, in one embodiment, the R¹⁷ Ar or Het is substituted with 1, 2or 3 substituents independently selected from —(C₁-C₃ alkyl), —(C₁-C₃haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰,-halogen, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰ is independentlyselected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl), —(C₀-C₂alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. In certain embodiments, R¹⁷ issubstituted with 1, 2 or 3 substituents selected from halo, cyano,—(C₁-C₄ haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄alkyl), —C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄alkyl)(C₀-C₄ alkyl), NO₂ and —C(O)—Hca. R¹⁷ can be substituted with, forexample, one such substituent, or two such substituents.

In certain embodiments, the presently disclosed compounds have thestructural formula (XXIII):

in which R²⁷ is selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl)(e.g., difluoromethyl, trifluoromethyl and the like), —(C₀-C₆alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl)-(C₀-C₆alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), in which no heterocycloalkyl, alkyl orhaloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group, and R²⁹ is —H, —(C₁-C₄ alkyl),—C(O)—(C₁-C₄ alkyl) or —C(O)—O—(C₁-C₄ alkyl) in which no (C₁-C₄ alkyl)is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group, or R²⁷ and R²⁹ together with thenitrogen to which they are bound form Hca, and all other variables areas described above with reference to any of structural formulae(I)-(XXII). In one embodiment, R²⁷ and R²⁹ are both H.

In certain embodiments, the presently disclosed compounds have thestructural formula (XXIV):

in which R²⁷ is selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl)(e.g., difluoromethyl, trifluoromethyl and the like), —(C₀-C₆alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl)-(C₀-C₆alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), in which no heterocycloalkyl, alkyl orhaloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group, and R²⁹ is —H, —(C₁-C₄ alkyl),—CO—O—(C₁-C₄ alkyl) or —CO—O—(C₁-C₄ alkyl) in which no (C₁-C₄ alkyl) issubstituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group, or R²⁷ and R²⁹ together with thenitrogen to which they are bound form Hca, and all other variables areas described above with reference to any of structural formulae(I)-(XXII). In one embodiment, R²⁷ and R²⁹ are both H.

In certain embodiments, the presently disclosed compounds have thestructural formula (XXV):

in which R²⁷ is selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl)(e.g., difluoromethyl, trifluoromethyl and the like), —(C₀-C₆alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl)-(C₀-C₆alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), in which no heterocycloalkyl, alkyl orhaloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group, and R²⁹ is —H, —(C₁-C₄ alkyl),—CO—O—(C₁-C₄ alkyl) or —CO—O—(C₁-C₄ alkyl) in which no (C₁-C₄ alkyl) issubstituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group, or R²⁷ and R²⁹ together with thenitrogen to which they are bound form Hca, and all other variables areas described above with reference to any of structural formulae(I)-(XXII). In one embodiment, R²⁷ and R²⁹ are both H.

In certain embodiments, the presently disclosed compounds have thestructural formula (XXVI):

in which R²⁷ is selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl)(e.g., difluoromethyl, trifluoromethyl and the like), —(C₀-C₆alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl)-(C₀-C₆alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), in which no heterocycloalkyl, alkyl orhaloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group, and R²⁹ is —H, —(C₁-C₄ alkyl),—CO—O—(C₁-C₄ alkyl) or —CO—O—(C₁-C₄ alkyl) in which no (C₁-C₄ alkyl) issubstituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group, or R²⁷ and R²⁹ together with thenitrogen to which they are bound form Hca, and all other variables areas described above with reference to any of structural formulae(I)-(XXII). In one embodiment, R²⁷ and R²⁹ are both H.

In certain embodiments, the presently disclosed compounds have thestructural formula (XXVII):

in which all variables are as described above with reference to any ofstructural formulae (I)-(XXII).

In certain embodiments, the presently disclosed compounds have thestructural formula (XXVIII):

in which R²⁵ is selected from halo, cyano, —(C₁-C₄ haloalkyl), —O—(C₁-C₄haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl), —C(O)—(C₀-C₄ alkyl),—C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), NO₂ and—C(O)—Hca in which the Hca contains a ring nitrogen atom through whichit is bound to the —C(O)—, in which no alkyl or haloalkyl is substitutedby an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group;and all other variables are as described above with reference to any ofstructural formulae (I)-(XXII). R²⁵ can be, for example, —Cl, —F, cyano,—C(O)CH₃, —C(O)OH, —C(O)NH₂, trifluoromethyl, difluoromethyl,difluoromethoxy or trifluoromethoxy.

In certain embodiments, the presently disclosed compounds have thestructural formula (XXIX):

in which G is —C(O)—, —S(O)₂— or —C(O)—NH— and all other variables areas described above with reference to any of structural formulae(I)-(XXII).

In certain embodiments, the presently disclosed compounds have thestructural formula (XXX):

in which R²⁷ is selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl)(e.g., difluoromethyl, trifluoromethyl and the like), —(C₀-C₆alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl)-(C₀-C₆alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), in which no heterocycloalkyl, alkyl orhaloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group, and R²⁹ is —H, —(C₁-C₄ alkyl),—CO—O—(C₁-C₄ alkyl) or —CO—O—(C₁-C₄ alkyl) in which no (C₁-C₄ alkyl) issubstituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group, or R²⁷ and R²⁹ together with thenitrogen to which they are bound form Hca, and all other variables areas described above with reference to any of structural formulae(I)-(XXII). In one embodiment, R²⁷ and R²⁹ are both H. In someembodiments, the compounds of structural formula (XXX) are present asracemic mixtures or scalemic mixtures. In other embodiments, thecompounds of structural formula (XXX) are present in anenantiomerically-enriched form, for example as a substantially purestereoisomer.

In certain embodiments, the presently disclosed compounds have thestructural formula (XXXI):

in which R²⁷ is selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl)(e.g., difluoromethyl, trifluoromethyl and the like), —(C₀-C₆alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl)-(C₀-C₆alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), in which no heterocycloalkyl, alkyl orhaloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group, and R²⁹ is —H, —(C₁-C₄ alkyl),—CO—O—(C₁-C₄ alkyl) or —CO—O—(C₁-C₄ alkyl) in which no (C₁-C₄ alkyl) issubstituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group, or R²⁷ and R²⁹ together with thenitrogen to which they are bound form Hca, and all other variables areas described above with reference to any of structural formulae(I)-(XXII). In one embodiment, R²⁷ and R²⁹ are both H. In someembodiments, the compounds of structural formula (XXXI) are present asracemic mixtures or scalemic mixtures. In other embodiments, thecompounds of structural formula (XXXI) are present in anenantiomerically-enriched form, for example as a substantially purestereoisomer.

In certain embodiments, the presently disclosed compounds have thestructural formula (XXXII):

in which G, v, R¹⁵ and R¹⁷ are defined as described above with referenceto structural formula (XXII), and all other variables are defined asdescribed above with reference to structural formulae (I) or (II). R⁵,y, v, R¹⁵, R¹⁷, Q, G and the ring denoted by “A” can be defined, forexample, as described with reference to any of structural formulae(XXIII)-(XXXI).

In certain embodiments, the presently disclosed compounds have thestructural formula (XXXIII):

in which G, v, R¹⁵ and R¹⁷ are defined as described above with referenceto structural formula (XXII), and all other variables are defined asdescribed above with reference to structural formulae (I) or (III). R⁵,y, v, R¹⁵, R¹⁷, Q, G and the ring denoted by “A” can be defined, forexample, as described with reference to any of structural formulae(XXIII)-(XXXI).

In certain embodiments, the presently disclosed compounds have thestructural formula (XXXIV):

in which J is —CH₂—, —CH(R²⁶)— or —C(R²⁶)₂— (e.g., —CH₂—), G, v, R¹⁵ andR¹⁷ are defined as described above with reference to structural formula(XXII), and all other variables are defined as described above withreference to structural formulae (I) or (IV). R⁵, y, v, R¹⁵, R¹⁷, Q, Gand the ring denoted by “A” can be defined, for example, as describedwith reference to any of structural formulae (XXIII)-(XXXI).

In certain embodiments, the presently disclosed compounds have thestructural formula (XXXV):

in which J is —CH₂—, —CH(R²⁶)— or —C(R²⁶)₂— (e.g., —CH₂—), G, v, R¹⁵ andR¹⁷ are defined as described above with reference to structural formula(XXII), and all other variables are defined as described above withreference to structural formulae (I) or (V). R⁵, y, v, R¹⁵, R¹⁷, Q, Gand the ring denoted by “A” can be defined, for example, as describedwith reference to any of structural formulae (XXIII)-(XXXI).

In certain embodiments, the presently disclosed compounds have thestructural formula (XXXVI):

in which G, v, R¹⁵ and R¹⁷ are defined as described above with referenceto structural formula (XXII), and all other variables are defined asdescribed above with reference to structural formulae (I) or (VI). R⁵,y, v, R¹⁵, R¹⁷, Q, G and the ring denoted by “A” can be defined, forexample, as described with reference to any of structural formulae(XXIII)-(XXXI).

In certain embodiments, the presently disclosed compounds have thestructural formula (XXXVII):

in which G, v, R¹⁵ and R¹⁷ are detmed as described above with reterenceto structural tormula (XXII), and all other variables are defined asdescribed above with reference to structural formulae (I) or (VII). R⁵,y, v, R¹⁵, R¹⁷, Q, G and the ring denoted by “A” can be defined, forexample, as described with reference to any of structural formulae(XXIII)-(XXXI).

In certain embodiments, the presently disclosed compounds have thestructural formula (XXXVIII):

in which one of X¹ and X² is N, and the other is a carbon; G, v, R¹⁵ andR¹⁷ are defined as described above with reference to structural formula(XXII), and all other variables are defined as described above withreference to structural formulae (I) or (VIII). R⁵, y, v, R¹⁵, R¹⁷, Q, Gand the ring denoted by “A” can be defined, for example, as describedwith reference to any of structural formulae (XXIII)-(XXXI). In oneembodiment, for example, X¹ is N and X² is a carbon. In anotherembodiment, X¹ is a carbon, and X² is N.

In certain embodiments, the presently disclosed compounds have thestructural formula (XXXIX):

in which in which one of X¹ and X² is N, and the other is a carbon; G,v, R¹⁵ and R¹⁷ are defined as described above with reference tostructural formula (XXII), and all other variables are defined asdescribed above with reference to structural formulae (I) or (IX). R⁵,y, v, R¹⁵, R¹⁷, Q, G and the ring denoted by “A” can be defined, forexample, as described with reference to any of structural formulae(XXIII)-(XXXI). In one embodiment, for example, X¹ is N and X² is acarbon. In another embodiment, X¹ is a carbon, and X² is N.

In certain embodiments, the presently disclosed compounds have thestructural formula (XL):

in which G, v, R¹⁵ and R¹⁷ are defined as described above with referenceto structural formula (XXII), and all other variables are defined asdescribed above with reference to structural formulae (I) or (X). R⁵, y,v, R¹⁵, R¹⁷, Q, G and the ring denoted by “A” can be defined, forexample, as described with reference to any of structural formulae(XXIII)-(XXXI). In certain embodiments, one R¹⁴ is substituted on thepyrrolo carbon. R¹⁴ can be, for example, as described above withreference to structural formula (I). For example, in one embodiment R¹⁴is halo (e.g., —Cl or —F), cyano unsubstituted —(C₁-C₄ alkyl) (e.g.,methyl or ethyl), unsubstituted —(C₁-C₄ haloakyl) (e.g., difluoromethyl,trifluoromethyl and the like). In other embodiments, no R¹⁴ issubstituted on the pyrrolo carbon.

In certain embodiments, the presently disclosed compounds have thestructural formula (XLI):

in which G, v, R¹⁵ and R¹⁷ are defined as described above with referenceto structural formula (XXII), and all other variables are defined asdescribed above with reference to structural formulae (I) or (XI). R⁵,y, v, R¹⁵, R¹⁷, Q, G and the ring denoted by “A” can be defined, forexample, as described with reference to any of structural formulae(XXIII)-(XXXI). In certain embodiments, one R¹⁴ is substituted on thepyrrolo carbon. R¹⁴ can be, for example, as described above withreference to structural formula (I). For example, in one embodiment R¹⁴is halo (e.g., —Cl or —F), cyano unsubstituted —(C₁-C₄ alkyl) (e.g.,methyl or ethyl), unsubstituted —(C₁-C₄ haloakyl) (e.g., difluoromethyl,trifluoromethyl and the like). In other embodiments, no R¹⁴ issubstituted on the pyrrolo carbon.

In certain embodiments of compounds having structural formulae(XXII)-(XLI), the

moiety has the structure

in which G is —CH₂—, —CH(CH₃)—, —C(O)—, —S(O)₂— or —C(O)—NH—. Forexample, in one embodiment, G is —CH₂—. In another embodiment, G is—C(O)— or —S(O)₂—. In another embodiment, G is —C(O)—NH—.

In other embodiments of compounds having structural formulae(XXII)-(XLI), the

moiety has the structure

in which G is —CH₂—, —C(O)—, —S(O)₂— or —C(O)—NH—, R²⁷ is selected fromH, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl) (e.g., difluoromethyl,trifluoromethyl and the like), —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆alkyl)-C(O)—(C₀-C₆ alkyl)-(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), in whichno heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-,heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R²⁹is —H, —(C₁-C₄ alkyl), —CO—(C₁-C₄ alkyl) or —CO—O—(C₁-C₄ alkyl) in whichno (C₁-C₄ alkyl) is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group, or R²⁷ and R²⁹ together with thenitrogen to which they are bound form Hca. In such embodiments, thecompounds can be present as racemic mixtures or scalemic mixtures, or inan enantiomerically-enriched form, for example as a substantially purestereoisomer.

In other embodiments of compounds having structural formulae(XXII)-(XLI), the

moiety has the structure

in which G is —CH₂—, —C(O)—, —S(O)₂— or —C(O)—NH—.

In certain embodiments of compounds having structural formulae(XXII)-(XLI), the R¹⁷ moiety has the structure

in which R²⁷ is selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl)(e.g., difluoromethyl, trifluoromethyl and the like), —(C₀-C₆alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl)-(C₀-C₆alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), in which no heterocycloalkyl, alkyl orhaloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group, and R²⁹ is —H, —(C₁-C₄ alkyl),—CO—(C₁-C₄ alkyl) or —CO—O—(C₁-C₄ alkyl) in which no (C₁-C₄ alkyl) issubstituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group, or R²⁷ and R²⁹ together with thenitrogen to which they are bound form Hca.

In certain embodiments of compounds having structural formulae(XXII)-(XLI), w is 1, and R³ is —NR⁸R⁹. In certain such embodiments, R³is substituted at a benzo, pyrido or pyrazino ring position in the metaposition relative to the J moiety.

In other embodiments of compounds having structural formulae(XXII)-(XLI), w is 1, and R³ is —(C₀-C₃ alkyl)-Y¹—(C₁-C₃alkyl)-Y²—(C₀-C₃ alkyl), in which each of Y¹ and Y² is independently L,—O—, —S— or —NR⁹—. In certain such embodiments, R³ is substituted at abenzo, pyrido or pyrazino ring position in the meta position relative tothe J moiety.

In certain embodiments described above, each R²⁷ is selected from—(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰—(C₀-C₃alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN and two R²¹ on the same carbonoptionally combine to form oxo, in which each R⁷, R⁸ and R¹⁰ isindependently selected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl),—(C₀-C₂ alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group, and each R²⁹ is H, methyl or ethyl,or R²⁷ and R²⁹ together with the nitrogen to which they are bound formHca.

In certain embodiments of compounds having structural formulae(XXII)-(XLI), at least one R⁵ moiety is a haloalkyl group, and inexemplary embodiments of these formulae the

moiety is p-(trifluoromethyl)phenyl. By way of further illustration,certain exemplary compounds including such

moieties have structural formula (XLII) or (XLIII):

in which all variables are as described above with reference tostructural formulae (XXXII) or (XXXIII).

In one embodiment, the presently disclosed compounds have the structuralformula (XLIV):

in which G, R¹, R³, R¹⁷ and R³⁸ are as described above with reference toany of structural formulae (I), (II), (XII) or (XXII), R¹⁸ is H, —(C₁-C₆alkyl), —(C₁-C₆ haloalkyl) (e.g., difluoromethyl, trifluoromethyl andthe like), —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆alkyl) and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), in which no alkyl orhaloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group and R¹⁹ is —H, —(C₁-C₄ alkyl),—CO—(C₁-C₄ alkyl) or —CO—O—(C₁-C₄ alkyl) in which no alkyl issubstituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group, or R¹⁸ and R¹⁹ together with thenitrogen to which they are bound form Hca. In one embodiment, R¹⁸ andR¹⁹ are both H.

In one embodiment, the presently disclosed compounds have the structuralformula (XLV):

in which G, R¹, R³, R¹⁷ and R³⁸ are as described above with reference toany of structural formulae (I), (III), (XIII) and (XXII), and R¹⁸ andR¹⁹ are defined as described above with reference to structural formula(XLIV).

In another embodiment, the presently disclosed compounds have thestructural formula (XLVI):

in which Q, R¹, R³, R⁵ and R³⁸ are defined as described above withreference to any of structural formulae (I), (II), (XII) and (XXII), andR¹⁸ and R¹⁹ are defined as described above with reference to structuralformula (XLIV).

In another embodiment, the presently disclosed compounds have thestructural formula (XLVII):

in which Q, R¹, R³, R⁵ and R³⁸ are defined as described above withreference to any of structural formulae (I), (III), (XIII) and (XXII),and R¹⁸ and R¹⁹ are defined as described above with reference tostructural formula (XLIV).

In another embodiment, the presently disclosed compounds have thestructural formula (XLVIII):

in which R¹, R³, R⁵ and R³⁸ are defined as described above withreference to any of structural formulae (I), (II), (XII) and (XXII), andR¹⁸ and R¹⁹ are defined as described above with reference to structuralformula (XLIV).

In another embodiment, the presently disclosed compounds have thestructural formula (XLIX):

in which R¹, R³, R⁵ and R³⁸ are defined as described above withreference to any of structural formulae (I), (III), (XIII) and (XXII),and R¹⁸ and R¹⁹ are defined as described above with reference tostructural formula (XLIV).

In compounds according to any of structural formulae (I), (IV) -(XI) and(XIV)-(XXI), T and R² can be defined as described above with referenceto structural formulae (XLIV)-(XLIX).

In certain embodiments, the presently disclosed compounds have thestructural formula (L):

in which Q is —CH₂—, —C(O)— or a single bond; G is a single bond, —CH₂—,—C(O)—, —S(O)₂— or —C(O)—NH—; R¹, R³ and R³⁸ are as described above withreference to any of structural formulae (I), (II), (XII) and (XXII); andR¹¹, R¹² and R¹³ are independently selected from H, halo, cyano, —(C₁-C₄haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl),—C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄alkyl), NO₂ and —C(O)—Hca in which the Hca contains a ring nitrogen atomthrough which it is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹¹, R¹² and R¹³ is not H. In one embodiment, R¹¹ isattached in the para position relative to the G moiety; in anotherembodiment, R¹¹ is attached in the meta position relative to the Gmoiety. In one embodiment, no R³ is substituted on the benzo moiety. Inanother embodiment, one R³ (e.g., —Cl, —F, —CH₃, —C₂H₅, —C₃H₇) issubstituted on the benzo moiety.

In certain embodiments, the presently disclosed compounds have thestructural formula (LI):

in which Q is —CH₂—, —C(O)— or a single bond; G is a single bond, —CH₂—,—C(O)—, —S(O)₂— or —C(O)—NH—; R¹, R³ and R³⁸ are as described above withreference to any of structural formulae (I), (II), (XII) and (XXII); andR¹² and R¹³ are independently selected from H, halo, cyano, —(C₁-C₄haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl),—C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄alkyl), NO₂ and —C(O)—Hca in which the Hca contains a ring nitrogen atomthrough which it is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹² and R¹³ is not H. In one embodiment, the pyridonitrogen is disposed in the para position relative to the G moiety; inanother embodiment, the pyrido nitrogen is disposed in the meta positionrelative to the G moiety. In one embodiment, no R³ is substituted on thebenzo moiety. In another embodiment, one R³ (e.g., —Cl, —F, —CH₃, —C₂H₅,—C₃H₇) is substituted on the benzo moiety.

In certain embodiments, the presently disclosed compounds have thestructural formula (LII):

in which Q is —CH₂—, —C(O)— or a single bond; G is a single bond, —CH₂—,—C(O)—, —S(O)₂— or —C(O)—NH—; R¹, R³ and R³⁸ are as described above withreference to any of structural formulae (I), (III), (XIII) and (XXII);and R¹¹, R¹² and R¹³ are independently selected from H, halo, cyano,—(C₁-C₄ haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄alkyl), —C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄alkyl)(C₀-C₄ alkyl), NO₂ and —C(O)—Hca in which the Hca contains a ringnitrogen atom through which it is bound to the —C(O)—, in which noalkyl, haloalkyl or heterocycloalkyl is substituted by an aryl,heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In oneparticular such embodiment, at least one of R¹¹, R¹² and R¹³ is not H.In one embodiment, R¹¹ is attached in the para position relative to theG moiety; in another embodiment, R¹¹ is attached in the meta positionrelative to the G moiety. In one embodiment, no R³ is substituted on thebenzo moiety. In another embodiment, one R³ (e.g., —Cl, —F, —CH₃, —C₂H₅,—C₃H₇) is substituted on the benzo moiety.

In certain embodiments, the presently disclosed compounds have thestructural formula (LIII):

in which Q is —CH₂—, —C(O)— or a single bond; G is a single bond, —CH₂—,—C(O)—, —S(O)₂— or —C(O)—NH—; R¹, R³ and R³⁸ are as described above withreference to any of structural formulae (I), (III), (XIII) and (XXII);R¹² and R¹³ are independently selected from H, halo, cyano, —(C₁-C₄haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl),—C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄alkyl), NO₂ and —C(O)—Hca in which the Hca contains a ring nitrogen atomthrough which it is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹² and R¹³ is not H. In one embodiment, the pyridonitrogen is disposed in the para position relative to the G moiety; inanother embodiment, the pyrido nitrogen is disposed in the meta positionrelative to the G moiety. In one embodiment, no R³ is substituted on thebenzo moiety. In another embodiment, one R³ (e.g., —Cl, —F, —CH₃, —C₂H₅,—C₃H₇) is substituted on the benzo moiety.

In one embodiment, the presently disclosed compounds have the structuralformula (LIV):

in which Q is —CH₂—, —C(O)— or a single bond; G is a single bond, —CH₂—,—C(O)—, —S(O)₂— or —C(O)—NH—; R¹ and R³ are as described above withrespect to any of structural formulae (I), (IV), (XIV) and (XXII); andR¹¹, R¹² and R¹³ are independently selected from H, halo, cyano, —(C₁-C₄haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl),—C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄alkyl), NO₂ and —C(O)—Hca in which the Hca contains a ring nitrogen atomthrough which it is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹¹, R¹² and R¹³ is not H. In one embodiment, R¹¹ isattached in the para position relative to the G moiety; in anotherembodiment, R¹¹ is attached in the meta position relative to the Gmoiety. In one embodiment, no R³ is substituted on the central phenylmoiety. In another embodiment, one R³ (e.g., —Cl, —F, —CH₃, —C₂H₅,—C₃H₇) is substituted on the central phenyl moiety.

In certain embodiments, the presently disclosed compounds have thestructural formula (LV):

in which Q is —CH₂—, —C(O)— or a single bond; G is a single bond, —CH₂—,—C(O)—, —S(O)₂— or —C(O)—NH—; R¹ and R³ are as described above withreference to any of structural formulae (I), (IV), (XIV) and (XXII); andR¹² and R¹³ are independently selected from H, halo, cyano, —(C₁-C₄haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl),—C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄alkyl), NO₂ and —C(O)—Hca in which the Hca contains a ring nitrogen atomthrough which it is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹² and R¹³ is not H. In one embodiment, the pyridonitrogen is disposed in the para position relative to the G moiety; inanother embodiment, the pyrido nitrogen is disposed in the meta positionrelative to the G moiety. In one embodiment, no R³ is substituted on thecentral phenyl moiety. In another embodiment, one R³ (e.g., —Cl, —F,—CH₃, —C₂H₅, —C₃H₇) is substituted on the central phenyl moiety.

In certain embodiments, the presently disclosed compounds have thestructural formula (LVI):

in which Q is —CH₂—, —C(O)— or a single bond; G is a single bond, —CH₂—,—C(O)—, —S(O)₂— or —C(O)—NH—; R¹ and R³ are as described above withrespect to any of structural formulae (I), (V), (XV) and (XXII); andR¹¹, R¹² and R¹³ are independently selected from H, halo, cyano, —(C₁-C₄haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl),—C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄alkyl), NO₂ and —C(O)—Hca in which the Hca contains a ring nitrogen atomthrough which it is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹¹, R¹² and R¹³ is not H. In one embodiment, R¹¹ isattached in the para position relative to the G moiety; in anotherembodiment, R¹¹ is attached in the meta position relative to the Gmoiety. In one embodiment, no R³ is substituted on the central phenylmoiety. In another embodiment, one R³ (e.g., —Cl, —F, —CH₃, —C₂H₅,—C₃H₇) is substituted on the central phenyl moiety.

In certain embodiments, the presently disclosed compounds have thestructural formula (LVII):

in which Q is —CH₂—, —C(O)— or a single bond; G is a single bond, —CH₂—,—C(O)—, —S(O)₂— or —C(O)—NH—; R¹ and R³ are as described above withreference to any of structural formulae (I), (V), (XV) and (XXII); andR¹² and R¹³ are independently selected from H, halo, cyano, —(C₁-C₄haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl),—C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄alkyl), NO₂ and —C(O)—Hca in which the Hca contains a ring nitrogen atomthrough which it is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹² and R¹³ is not H. In one embodiment, the pyridonitrogen is disposed in the para position relative to the G moiety; inanother embodiment, the pyrido nitrogen is disposed in the meta positionrelative to the G moiety. In one embodiment, no R³ is substituted on thecentral phenyl moiety. In another embodiment, one R³ (e.g., —Cl, —F,—CH₃, —C₂H₅, —C₃H₇) is substituted on the central phenyl moiety.

In certain embodiments, the presently disclosed compounds have thestructural formula (LVIII):

in which Q is —CH₂—, —C(O)— or a single bond; G is a single bond, —CH₂—,—C(O)—, —S(O)₂— or —C(O)—NH—; R¹ and R³ are as described above withreference to any of structural formulae (I), (VI), (XVI) and (XXII); andR¹¹, R¹² and R¹³ are independently selected from H, halo, cyano, —(C₁-C₄haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl),—C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄alkyl), NO₂ and —C(O)—Hca in which the Hca contains a ring nitrogen atomthrough which it is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹¹, R¹² and R¹³ is not H. In one embodiment, R¹¹ isattached in the para position relative to the G moiety; in anotherembodiment, R¹¹ is attached in the meta position relative to the Gmoiety. In one embodiment, no R³ is substituted on the naphthyl moiety.In another embodiment, one R³ (e.g., —Cl, —F, —CH₃, —C₂H₅, —C₃H₇) issubstituted on the naphthyl moiety.

In certain embodiments, the presently disclosed compounds have thestructural formula (LIX):

in which Q is —CH₂—, —C(O)— or a single bond; G is a single bond, —CH₂—,—C(O)—, —S(O)₂— or —C(O)—NH—; R¹ and R³ are as described above withreference to structural formulae (I), (VI), (XVI) and (XXII); and R¹²and R¹³ are independently selected from H, halo, cyano, —(C₁-C₄haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl),—C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄alkyl), NO₂ and —C(O)—Hca in which the Hca contains a ring nitrogen atomthrough which it is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹² and R¹³ is not H. In one embodiment, the pyridonitrogen is disposed in the para position relative to the G moiety; inanother embodiment, the pyrido nitrogen is disposed in the meta positionrelative to the G moiety. In one embodiment, no R³ is substituted on thenaphthyl moiety. In another embodiment, one R³ (e.g., —Cl, —F, —CH₃,—C₂H₅, —C₃H₇) is substituted on the naphthyl moiety.

In certain embodiments, the presently disclosed compounds have thestructural formula (LX):

in which Q is —CH₂—, —C(O)— or a single bond; G is a single bond, —CH₂—,—C(O)—, —S(O)₂— or —C(O)—NH—; R¹ and R³ are as described above withreference to any of structural formulae (I), (VII), (XVII) and (XXII);and R¹¹, R¹² and R¹³ are independently selected from H, halo, cyano,—(C₁-C₄ haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄alkyl), —C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄alkyl)(C₀-C₄ alkyl), NO₂ and —C(O)-Hca in which the Hca contains a ringnitrogen atom through which it is bound to the —C(O)—, in which noalkyl, haloalkyl or heterocycloalkyl is substituted by an aryl,heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In oneparticular such embodiment, at least one of R¹¹, R¹² and R¹³ is not H.In one embodiment, R¹¹ is attached in the para position relative to theG moiety; in another embodiment, R¹¹ is attached in the meta positionrelative to the G moiety. In one embodiment, no R³ is substituted on thenaphthyl moiety. In another embodiment, one R³ (e.g., —Cl, —F, —CH₃,—C₂H₅, —C₃H₇) is substituted on the naphthyl moiety.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXI):

in which Q is —CH₂—, —C(O)— or a single bond; G is a single bond, —CH₂—,—C(O)—, —S(O)₂— or —C(O)—NH—; R¹ and R³ are as described above withreference to structural formulae (I), (VII), (XVII) and (XXII); and R¹²and R¹³ are independently selected from H, halo, cyano, —(C₁-C₄haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl),—C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄alkyl), NO₂ and —C(O)—Hca in which the Hca contains a ring nitrogen atomthrough which it is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹² and R¹³ is not H. In one embodiment, the pyridonitrogen is disposed in the para position relative to the G moiety; inanother embodiment, the pyrido nitrogen is disposed in the meta positionrelative to the G moiety. In one embodiment, no R³ is substituted on thenaphthyl moiety. In another embodiment, one R³ (e.g., —Cl, —F, —CH₃,—C₂H₅, —C₃H₇) is substituted on the naphthyl moiety.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXII):

in which one of X¹ and X² is N and the other is a carbon; Q is —CH₂—,—C(O)— or a single bond; G is a single bond, —CH₂—, —C(O)—, —S(O)₂— or—C(O)—NH—; R¹ and R³ are as described above with reference to any ofstructural formulae (I), (VIII), (XVIII) and (XXII); and R¹¹, R¹² andR¹³ are independently selected from H, halo, cyano, —(C₁-C₄ haloalkyl),—O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl), —C(O)—(C₀-C₄alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), NO₂ and—C(O)—Hca in which the Hca contains a ring nitrogen atom through whichit is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹¹, R¹² and R¹³ is not H. In one embodiment, R¹¹ isattached in the para position relative to the G moiety; in anotherembodiment, R¹¹ is attached in the meta position relative to the Gmoiety. In one embodiment, no R³ is substituted on the quinolinylmoiety. In another embodiment, one R³ (e.g., —Cl, —F, —CH₃, —C₂H₅,—C₃H₇) is substituted on the quinolinyl moiety.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXIII):

in which one of X¹ and X² is N and the other is a carbon; Q is —CH₂—,—C(O)— or a single bond; G is a single bond, —CH₂—, —C(O)—, —S(O)₂— or—C(O)—NH—; R¹ and R³ are as described above with reference to structuralformulae (I), (VIII), (XVIII) and (XXII); and R¹² and R¹³ areindependently selected from H, halo, cyano, —(C₁-C₄ haloalkyl),—O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl), —C(O)—(C₀-C₄alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), NO₂ and—C(O)—Hca in which the Hca contains a ring nitrogen atom through whichit is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹² and R¹³ is not H. In one embodiment, the pyridonitrogen is disposed in the para position relative to the G moiety; inanother embodiment, the pyrido nitrogen is disposed in the meta positionrelative to the G moiety. In one embodiment, no R³ is substituted on thequinolinyl moiety. In another embodiment, one R³ (e.g., —Cl, —F, —CH₃,—C₂H₅, —C₃H₇) is substituted on the quinolinyl moiety.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXIV):

in which one of X¹ and X² is N and the other is a carbon; Q is —CH₂—,—C(O)— or a single bond; G is a single bond, —CH₂—, —C(O)—, —S(O)₂— or—C(O)—NH—; R¹ and R³ are as described above with reference to any ofstructural formulae (I), (IX), (XIX) and (XXII); and R¹¹, R¹² and R¹³are independently selected from H, halo, cyano, —(C₁-C₄ haloalkyl),—O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl), —C(O)—(C₀-C₄alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), NO₂ and—C(O)—Hca in which the Hca contains a ring nitrogen atom through whichit is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹¹, R¹² and R¹³ is not H. In one embodiment, R¹¹ isattached in the para position relative to the G moiety; in anotherembodiment, R¹¹ is attached in the meta position relative to the Gmoiety. In one embodiment, no R³ is substituted on the quinolinylmoiety. In another embodiment, one R³ (e.g., —Cl, —F, —CH₃, —C₂H₅,—C₃H₇) is substituted on the quinolinyl moiety.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXV):

in which one of X¹ and X² is N and the other is a carbon; Q is —CH₂—,—C(O)— or a single bond; G is a single bond, —CH₂—, —C(O)—, —S(O)₂— or—C(O)—NH—; R¹ and R³ are as described above with reference to structuralformulae (I), (IX), (XIX) and (XXII); and R¹² and R¹³ are independentlyselected from H, halo, cyano, —(C₁-C₄ haloalkyl), —O—(C₁-C₄ haloalkyl),—(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl), —C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), NO₂ and —C(O)—Hca in which theHca contains a ring nitrogen atom through which it is bound to the—C(O)—, in which no alkyl, haloalkyl or heterocycloalkyl is substitutedby an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group.In one particular such embodiment, at least one of R¹² and R¹³ is not H.In one embodiment, the pyrido nitrogen is disposed in the para positionrelative to the G moiety; in another embodiment, the pyrido nitrogen isdisposed in the meta position relative to the G moiety. In oneembodiment, no R³ is substituted on the quinolinyl moiety. In anotherembodiment, one R³ (e.g., —Cl, —F, —CH₃, —C₂H₅, —C₃H₇) is substituted onthe quinolinyl moiety.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXVI):

in which Q is —CH₂—, —C(O)— or a single bond; G is a single bond, —CH₂—,—C(O)—, —S(O)₂— or —C(O)—NH—; R¹, R³ and R³⁹ are as described above withreference to any of structural formulae (I), (X), (XX) and (XXII); R¹⁴is as described above with reference to structural formulae (I), (X),(XX) and (XXII) (e.g., absent, methyl or halo); and R¹¹, R¹² and R¹³ areindependently selected from H, halo, cyano, —(C₁-C₄ haloalkyl),—O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl), —C(O)—(C₀-C₄alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), NO₂ and—C(O)-Hca in which the Hca contains a ring nitrogen atom through whichit is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹¹, R¹² and R¹³ is not H. In one embodiment, R¹¹ isattached in the para position relative to the G moiety; in anotherembodiment, R¹¹ is attached in the meta position relative to the Gmoiety. In one embodiment, no R³ is substituted on the benzo moiety. Inanother embodiment, one R³ (e.g., —Cl, —F, —CH₃, —C₂H₅, —C₃H₇) issubstituted on the benzo moiety.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXVII):

in which Q is —CH₂—, —C(O)— or a single bond; G is a single bond, —CH₂—,—C(O)—, —S(O)₂— or —C(O)—NH—; R¹, R³ and R³⁹ are as described above withreference to any of structural formulae (I), (X), (XX) and (XXII); R¹⁴is as described above with reference to structural formulae (I), (X),(XX) and (XXII) (e.g., absent, methyl or halo); and R¹² and R¹³ areindependently selected from H, halo, cyano, —(C₁-C₄ haloalkyl),—O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl), —C(O)—(C₀-C₄alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), NO₂ and—C(O)—Hca in which the Hca contains a ring nitrogen atom through whichit is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹² and R¹³ is not H. In one embodiment, the pyridonitrogen is disposed in the para position relative to the G moiety; inanother embodiment, the pyrido nitrogen is disposed in the meta positionrelative to the G moiety. In one embodiment, no R³ is substituted on thebenzo moiety. In another embodiment, one R³ (e.g., —Cl, —F, —CH₃, —C₂H₅,—C₃H₇) is substituted on the benzo moiety.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXVIII):

in which Q is —CH₂—, —C(O)— or a single bond; G is a single bond, —CH₂—,—C(O)—, —S(O)₂— or —C(O)—NH—; R¹, R³ and R³⁹ are as described above withreference to any of structural formulae (I), (XI), (XXI) and (XXII); R¹⁴is as described above with reference to structural formulae (I), (XI),(XXI) and (XXII) (e.g., absent, methyl or halo); and R¹¹, R¹² and R¹³are independently selected from H, halo, cyano, —(C₁-C₄ haloalkyl),—O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl), —C(O)—(C₀-C₄alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), NO₂ and—C(O)-Hca in which the Hca contains a ring nitrogen atom through whichit is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹¹, R¹² and R¹³ is not H. In one embodiment, R¹¹ isattached in the para position relative to the G moiety; in anotherembodiment, R¹¹ is attached in the meta position relative to the Gmoiety. In one embodiment, no R³ is substituted on the benzo moiety. Inanother embodiment, one R³ (e.g., —Cl, —F, —CH₃, —C₂H₅, —C₃H₇) issubstituted on the benzo moiety.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXIX):

in which Q is —CH₂—, —C(O)— or a single bond; G is a single bond, —CH₂—,—C(O)—, —S(O)₂— or —C(O)—NH—; R¹, R³ and R³⁹ are as described above withreference to any of structural formulae (I), (X), (XX) and (XXII); R¹⁴is as described above with reference to structural formulae (I), (X),(XX) and (XXII) (e.g., absent, methyl or halo); and R¹² and R¹³ areindependently selected from H, halo, cyano, —(C₁-C₄ haloalkyl),—O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl), —C(O)—(C₀-C₄alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), NO₂ and—C(O)—Hca in which the Hca contains a ring nitrogen atom through whichit is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹² and R¹³ is not H. In one embodiment, the pyridonitrogen is disposed in the para position relative to the G moiety; inanother embodiment, the pyrido nitrogen is disposed in the meta positionrelative to the G moiety. In one embodiment, no R³ is substituted on thebenzo moiety. In another embodiment, one R³ (e.g., —Cl, —F, —CH₃, —C₂H₅,—C₃H₇) is substituted on the benzo moiety.

In one embodiment of the presently disclosed compounds of any ofstructural formulae (I)-(XXI), the compound has the structural formula(XXII), in which the “A” ring system is an aryl or heteroaryl; E is—C(O)— or —S(O)₂—, and in which the compound has a computed low energythree-dimensional conformer in which

-   -   the oxygen of the E —C(O)— group is positioned at (0 Å, 0 Å, 0        Å), or one of the oxygens of the E —S(O)₂— group is positioned        at (0 Å, 0 Å, 0 Å);    -   the centerpoint of an aromatic ring of the aryl or heteroaryl of        the “B” ring system is positioned within 3.5 Å of (−3.1 Å, 0.4        Å, 1.2 Å);    -   the nitrogen of the right-hand azacycloalkyl (i.e., the ring to        which -G-R¹⁷ is bound) is positioned within 3.5 Å of (0.8 Å, 1.6        Å, -5.3 Å);    -   the centerpoint of the left-hand azacycloalkyl (i.e., the ring        to which -Q-(A ring)-(R⁵)_(y) is bound) is positioned within 3.5        Å of (−6.2 Å, 0.1 Å, 7.4 Å); and    -   the centerpoint of an aromatic ring of the aryl or heteroaryl of        the “A” ring system is positioned within 3.5 Å of (−7.4 Å, −1.9        Å, 10.7 Å).

In certain embodiments of the presently disclosed compounds ofstructural formula (XXII), in a computed low energy three-dimensionalconformer:

-   -   the oxygen of the E —C(O)— group is positioned at (0 Å, 0 Å, 0        Å), or one of the oxygens of the E —S(O)₂— group is positioned        at (0 Å, 0 Å, 0 Å);    -   the centerpoint of an aromatic ring of the aryl or heteroaryl of        the “B” ring system is positioned within 2.5 Å of (−3.1 Å, 0.4        Å, 1.2 Å);    -   the nitrogen of the right-hand azacycloalkyl is positioned        within 1.8 Å of (0.8 Å, 1.6 Å, −5.3 Å);    -   the centerpoint of the left-hand azacycloalkyl is positioned        within 2.5 Å of (−6.2 Å, 0.1 Å, 7.4 Å); and    -   the centerpoint of an aromatic ring of the aryl or heteroaryl of        the “A” ring system is positioned within 2.5 Å of (−7.4 Å, −1.9        Å, 10.7 Å).

In one embodiment of the presently disclosed compounds of structuralformula (XXII), the “A” ring system is an aryl or heteroaryl substitutedwith a hydrophobic moiety; R¹⁷ is substituted with an electron acceptor;E is —C(O)— or —S(O)₂—, and the compound has a computed low energythree-dimensional conformer in which

-   -   the oxygen of the E —C(O)— group is positioned at (0 Å, 0 Å, 0        Å), or one of the oxygens of the E —S(O)₂— group is positioned        at (0 Å, 0 Å, 0 Å);    -   the centerpoint of an aromatic ring of the aryl or heteroaryl of        the “B” ring system is positioned within 3.5 Å of (−3.1 Å, 0.4        Å, 1.2 Å);    -   the nitrogen of the right-hand azacycloalkyl is positioned        within 3.5 Å of (0.8 Å, 1.6 Å, −5.3 Å);    -   the centerpoint of the left-hand azacycloalkyl is positioned        within 3.5 Å of (−6.2 Å, 0.1 Å, 7.4 Å); and    -   the centerpoint of an aromatic ring of the aryl or heteroaryl of        the “A” ring system is positioned within 3.5 Å of (−7.4 Å, −1.9        Å, 10.7 Å);    -   the hydrophobic moiety substituted on the “A” ring system is        positioned within 3.5 Å of (−9.0 Å, −3.2 Å, 13.4 Å); and    -   the electron acceptor substituted on R¹⁷ is positioned within        3.5 Å of (7.0 Å, −2.7 Å, −7.0 Å).        The hydrophobic moiety can be, for example, any of the        following, as defined in SMARTS query format:

#INCLUDE [a]F group(2) [a]Cl group(2) [a]Br group(2) [a]I group(2)[a]C(F)(F)(F) group(2,3,4,5) [a][CH2]C(F)(F)(F) group(2,3,4,5,6)[a]O[CH3] group(2,3) [a]S[CH3] group(2,3)[a]OC(F)(F)(F) group(2,3,4,5,6) C(F)(F)(F) group F group Cl groupBr group I group default_aromatic_surface groupdefault_aliphatic_surface group C[S;X2]C group [S;X2]CC group[S;X2]C group.The electron acceptor can be, for example, any of the following, asdefined in SMARTS query format:

#INCLUDE [N;X1]#[#6] vector(1) [N;X1]#CC vector(1)[N;X2](═C~[C,c])C vector(1) [N;X2](O)═N[a] vector(1)[N;X2](═N—O)[a] vector(1) [n;X2]1ccccc1 vector(1)[n;X2]([a])([a]) vector(1) [N;X2](═C~[C,c])(~[*]) vector(1)[N;X3](C)(C)[N;X3]C vector(1) [N;X2](═C)(~[*]) vector(1)[N;X2](~[C,c])═[N;X2] vector(1) [n;X2]1c[nH]cc1 vector(1)O═[S;X4](═O)([!#8])([!#8]) vector(1) [O;X2]C vector(1) [O;X2]N vector(1)[O;X1]═[C,c] vector(1) o vector(1) [O;X2](C)C vector(1)[O;X2]c1ncccc1 vector(1) [O;X2]~[a] vector(1) O═PO([!#1]) vector(1)[O;X2] vector(1) [S;X2](C)C vector(1) [S;X2](═C)N vector(1) #EXCLUDEO═C[O—,OH] point [O—,OH]C(═O) point [nH]([a])[a] point[#7;X3][*]═[O,S] point [N;X3](C)(C)[C;X3] point [N;X3][a] pointN(═N═N)[#6] point [NH2](C(═O)[NH2]) point [NH](C═O)(C═O) point[NH2](S(═O)(═O)[#6])[#6] point [NH](S(═O)(═O)[#6])[#6] pointn1c([NH2])ccnc1([NH2]) point o1nccc1 point o1cncc1 point o1cccc1 point[O;X2]C═O point [O;X2] point.

In one embodiment of the presently disclosed compounds of structuralformula (XXII), the “A” ring system is an aryl or heteroaryl substitutedwith a hydrophobic moiety; R¹⁷ is substituted with an electron acceptor;E is —C(O)— or —S(O)₂—, and the compound has a computed low energythree-dimensional conformer in which

-   -   the oxygen of the E —C(O)— group is positioned at (0 Å, 0 Å, 0        Å), or one of the oxygens of the E —S(O)₂— group is positioned        at (0 Å, 0 Å, 0 Å);    -   the centerpoint of an aromatic ring of the aryl or heteroaryl of        the “B” ring system is positioned within 2.5 Å of (−3.1 Å, 0.4        Å, 1.2 Å);    -   the nitrogen of the right-hand azacycloalkyl is positioned        within 1.8 Å of (0.8 Å, 1.6 Å, −5.3 Å);    -   the centerpoint of the left-hand azacycloalkyl is positioned        within 2.5 Å of (−6.2 Å, 0.1 Å, 7.4 Å); and    -   the centerpoint of an aromatic ring of the aryl or heteroaryl of        the “A” ring system is positioned within 2.5 Å of (−7.4 Å, −1.9        Å, 10.7 Å);    -   the hydrophobic moiety substituted on the “A” ring system is        positioned within 2.5 Å of (−9.0 Å, −3.2 Å, 13.4 Å); and    -   the electron acceptor substituted on R¹⁷ is positioned within 2        Å of (7.0 Å, −2.7 Å, −7.0 Å).

In certain embodiments of the presently disclosed compounds, thecomputed low energy three-dimensional conformer has a root mean squaredeviation from the given points of no greater than 3 Å, and a vectorscore greater than 0.2.

In certain embodiments of the presently disclosed compounds, thecomputed low energy three-dimensional conformer has a root mean squaredeviation from the given points of no greater than 1.5 Å, and a vectorscore greater than 0.4.

In certain embodiments of the presently disclosed compounds, thecomputed lowenergy three-dimensional conformer has a root mean squaredeviation from the given points of no greater than 1.2 Å, and a vectorscore greater than 0.5.

A centerpoint of a carbocyclic or heterocyclic ring is the averageposition of the constituent atoms of the ring (i.e., excluding anysubstituents) as positioned in the low energy three-dimensionalconformer. For example, the centerpoint of the left-hand azacycloalkylis the average position of its ring carbon and nitrogen atom(s).Similarly, the centerpoint of a phenyl ring is the average position ofits six ring carbons. Centerpoints are calculated only on single rings;multi-ring systems have multiple centerpoints, one for each ring. Forexample, a benzofuran would have two centerpoints, one calculated as theaverage position of the six carbon rings making up the fused benzenesubunit, and the other calculated as the average position of the fourcarbon atoms and one oxygen atom making up the fused furan subunit.

Low energy three-dimensional conformers can be calculated using thePhase software package version 3.0, available from Schrödinger LLC. Lowenergy three-dimensional conformers can be generated by a torsion searchprocedure under OPLS 2005 force field with a distance dependentdielectric constant. As the person of skill in the art will appreciate,the low energy conformer should be translated and rotated so that theoxygen of the E —C(O)— group is positioned at (0 Å, 0 Å, 0 Å), or one ofthe oxygens of the E —S(O)₂— group is positioned at (0 Å, 0 Å, 0 Å), andso that the root mean square deviation of the rest of the listedfeatures with respect to the given points is minimized.

As the person of skill in the art will recognize, the variousembodiments described above can be combined to form other embodiments ofthe invention. For example, in one embodiment, Q is —CH₂—, as describedabove, and G is —CH₂—, as described above. In another embodiment, thering system denoted by “A” is a phenyl, the ring system denoted by “B”is a phenyl, J is —N(R³⁸)—, D is a carbon, the dotted line denoted by“a” is a bond and the dotted line denoted by “b” is a single bond, asdescribed above.

Examples of compounds according to structural formula (I) include thoselisted in Table 1. These compounds can be made according to the generalschemes described below, for example using procedures analogous to thosedescribed below in the Examples.

TABLE 1 No. Name Structure 1 benzyl 8-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)-3,4-dihydro-1H-pyrido[4,3- b]indole-2(5H)-carboxylate

2 benzyl 8-(1-(4-benzyl)piperidin-4-ylcarbamoyl)-3,4-dihydro-1H-pyrido[4,3- b]indole-2(5H)-carboxylate

3 benzyl 8-(1-(tert-butoxycarbonyl)piperidin-4-ylcarbamoyl)-3,4-dihydro-1H- pyrido[4,3-b]indole-2(5H)-carboxylate

4 2-benzyl-N-(1-(4-cyanobenzyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3- b]indole-8-carboxamide

5 2-benzyl-N-(1-(4- trifluoromethylbenzyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole- 8-carboxamide

6 tert-butyl 4-(2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate

7 2-benzyl-N-(1-(pyridin-4- ylmethyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide

8 2-(4-fluorobenzyl)-N-(1-(pyridin-3- ylmethyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide

9 N-(1-(4-cyanobenzyl)piperidin-4-yl)-2-(4-fluorobenzyl)-2,3,4,5-tetrahydro-1H- pyrido[4,3-b]indole-8-carboxamide

10 N-(1-(4-trifluoromethylbenzyl)piperidin-4-yl)-2-(4-fluorobenzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide

11 N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide

12 N-(1-(4-cyanobenzyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide

13 N-(1-(4-trifluoromethylbenzyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide

14 N-(1-phenethylpiperidin-4-yl)-2-(4- (trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide

15 N-(1-(4-fluorophenyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide

16 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-methyl-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole- 8-carboxamide

17 N-(1-(4-trifluoromethylbenzyl)piperidin-4-yl)-5-methyl-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole- 8-carboxamide

18 5-methyl-N-(1-(pyridin-3- ylmethyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide

19 N-(1-benzylpiperidin-4-yl)-2-(4-(trifluoromethyl)phenylsulfonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide

20 5-acetyl-N-(1-(pyridin-3- ylmethyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide

21 N-(1-(4-cyanophenylsulfonyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide

22 N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide

23 2-(4-(trifluoromethyl)benzyl)-N-(1-(4-(trifluoromethyl)phenylsulfonyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3- b]indole-8-carboxamide

24 N-(1-(4-cyanobenzyl)piperidin-4-yl)-2-(4-(trifluoromethyl)phenylsulfonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide

25 N-(1-(4-cyanobenzyl)piperidin-4-yl)-2-(4-cyanophenylsulfonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide

26 N-(1-(4-cyanobenzyl)piperidin-4-yl)-2-(pyridin-3-ylsulfonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide

27 N-(1-(4-cyanophenylcarbamoyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide

28 N-(1-(4-fluorophenylsulfonyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide

29 N-(1-(3-cyanophenylsulfonyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide

30 2-(4-(trifluoromethyl)benzyl)-N-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3- b]indole-8-carboxamide

31 N-(1-(3-fluorophenylcarbamoyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide

32 N-(1-(4-chlorophenylsulfonyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide

33 2-(4-(trifluoromethyl)benzyl)-N-(1-(4-(trifluoromethyl)phenylcarbamoyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3- b]indole-8-carboxamide

34 N-(1-(4-cyanobenzyl)piperidin-4-yl)-2-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H- pyrido[4,3-b]indole-8-carboxamide

35 2-(4-fluorophenyl)-N-(1-(4- fluorophenylsulfonyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole- 8-carboxamide

36 2-(4-fluorophenyl)-N-(1-(pyridin-3- ylmethyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide

37 2-(4-fluorophenyl)-N-(1-(4- (trifluoromethyl)benzyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole- 8-carboxamide

38 tert-butyl 4-(2-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate

39 N-(1-(4-fluorobenzoyl)piperidin-4-yl)-2-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H- pyrido[4,3-b]indole-8-carboxamide

40 2-(4-fluorophenyl)-N-(1- nicotinoylpiperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide

41 2-(4-fluorophenyl)-N-(1-(4- (trifluoromethyl)benzoyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole- 8-carboxamide

42 N-(1-nicotinoylpiperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide

43 tert-butyl 4-(2-(4-carbamoylbenzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate

44 2-(4-carbamoylbenzyl)-N-(1-(4- cyanobenzyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide

45 2-(4-carbamoylbenzyl)-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide

46 2-(4-carbamoylbenzyl)-N-(1- isonicotinoylpiperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide

47 2-(4-carbamoylbenzyl)-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole- 8-carboxamide

48 2-(4-carbamoylbenzyl)-N-(1-(4- fluorobenzyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide

49 2-(4-carbamoylbenzyl)-N-(1-(4-carbamoylbenzyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide

50 N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide

51 N-(1-isonicotinoylpiperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide

52 N-(1-(4-carbamoylbenzyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide

53 N-(1-((1-methyl-1H-imidazol-4- yl)methyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide

54 N-(1-(oxazol-4-ylmethyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8- carboxamide

55 4-((4-benzylpiperazin-1-yl)methyl)-N-(1-benzylpiperidin-4-yl)benzamide

56 N-(1-benzylpiperidin-4-yl)-4-((4- (cyclohexylmethyl)piperazin-1-yl)methyl)benzamide

57 N-(1-benzylpiperidin-4-yl)-4-((4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1- yl)methyl)benzamide

58 N-(1-benzylpiperidin-4-yl)-4-((4-(pyridin-2-yl)piperazin-1-yl)methyl)benzamide

59 4-((4-benzylpiperazin-1-yl)methyl)-N-(1-(pyridin-4-ylmethyl)piperidin-4- yl)benzamide

60 4-((4-benzylpiperazin-1-yl)methyl)-N-(1-(pyridin-3-ylmethyl)piperidin-4- yl)benzamide

61 4-((4-benzylpiperazin-1-yl)methyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)benzamide

62 4-((4-benzylpiperazin-1-yl)methyl)-N-(1-(4-trifluoromethylbenzyl)piperidin-4- yl)benzamide

63 N-(1-benzylpiperidin-4-yl)-6-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yloxy)- 2-naphthamide

64 N-(1-benzylpiperidin-4-yl)-6-(1-(4- cyanobenzyl)piperidin-4-yloxy)-2-naphthamide

65 N-(1-benzylpiperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4- yloxy)-2-naphthamide

66 tert-butyl 4-(7-(1-(4- (trifluoromethyl)phenyl)piperidin-4-yloxy)-2-naphthamido)piperidine-1- carboxylate

67 tert-butyl 4-(6-(1-(4- (trifluoromethyl)phenyl)piperidin-4-yloxy)quinoline-3-carboxamido)piperidine- l-carboxylate

68 N-(piperidin-4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin-4-yloxy)quinoline-3-carboxamide

69 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4- yloxy)quinoline-3-carboxamide

70 N-(1-(4-(trifluoromethyl)benzyl)piperidin- 4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4- yloxy)quinoline-3-carboxamide

71 N-(1-benzylpiperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4- yloxy)quinoline-3-carboxamide

72 N-(1-benzylpiperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4- yloxy)-1H-indole-2-carboxamide

For simplicity, chemical moieties are defined and referred to throughoutprimarily as univalent chemical moieties (e.g., alkyl, aryl, etc.).Nevertheless, such terms are also used to convey correspondingmultivalent moieties under the appropriate structural circumstancesclear to those skilled in the art. For example, while an “alkyl” moietycan refer to a monovalent radical (e.g. CH₃—CH₂—), in some circumstancesa bivalent linking moiety can be “alkyl,” in which case those skilled inthe art will understand the alkyl to be a divalent radical (e.g.,—CH₂—CH₂—), which is equivalent to the term “alkylene.” (Similarly, incircumstances in which a divalent moiety is required and is stated asbeing “aryl,” those skilled in the art will understand that the term“aryl” refers to the corresponding divalent moiety, arylene). All atomsare understood to have their normal number of valences for bondformation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S,depending on the oxidation state of the S). Nitrogens in the presentlydisclosed compounds can be hypervalent, e.g., an N-oxide ortetrasubstituted ammonium salt. On occasion a moiety may be defined, forexample, as (A)_(a)-B—, wherein a is 0 or 1. In such instances, when ais 0 the moiety is B— and when a is 1 the moiety is A-B—.

As used herein, the term “alkyl” includes alkyl, alkenyl and alkynylgroups of a designed number of carbon atoms, desirably from 1 to about12 carbons (i.e., inclusive of 1 and 12). The term “C_(m)-C_(n) alkyl”means an alkyl group having from m to n carbon atoms (i.e., inclusive ofm and n). The term “C_(m)-C_(n) alkyl” means an alkyl group having fromm to n carbon atoms. For example, “C₁-C₆ alkyl” is an alkyl group havingfrom one to six carbon atoms. Alkyl and alkyl groups may be straight orbranched and depending on context, may be a monovalent radical or adivalent radical (i.e., an alkylene group). In the case of an alkyl oralkyl group having zero carbon atoms (i.e., “C₀ alkyl”), the group issimply a single covalent bond if it is a divalent radical or is ahydrogen atom if it is a monovalent radical. For example, the moiety“—(C₀-C₆ alkyl)-Ar” signifies connection of an optionally substitutedaryl through a single bond or an alkylene bridge having from 1 to 6carbons. Examples of “alkyl” include, for example, methyl, ethyl,propyl, isopropyl, butyl, iso-, sec- and tert-butyl, pentyl, hexyl,heptyl, 3-ethylbutyl, 3-hexenyl and propargyl. If the number of carbonatoms is not specified, the subject “alkyl” or “alkyl” moiety has from 1to 12 carbons.

The term “haloalkyl” is an alkyl group substituted with one or morehalogen atoms, e.g. F, Cl, Br and I. A more specific term, e.g.,“fluoroalkyl” is an alkyl group substituted with one or more fluorineatoms. Examples of “fluoroalkyl” include fluoromethyl, difluoromethyl,trifluoromethyl, pentafluoroethyl, hexafluoroisopropyl and the like. Incertain embodiments of the compounds disclosed herein, each haloalkyl isa fluoroalkyl.

The term “aryl” represents an aromatic carbocyclic ring system having asingle ring (e.g., phenyl) which is optionally fused to other aromatichydrocarbon rings or non-aromatic hydrocarbon rings. “Aryl” includesring systems having multiple condensed rings and in which at least oneis aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl). Examples ofaryl groups include phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl,dihydronaphthyl, fluorenyl, tetralinyl, 2,3-dihydrobenzofuranyl and6,7,8,9-tetrahydro-5H-benzo[α]cycloheptenyl. The aryl groups herein areunsubstituted or, when specified as “optionally substituted”, can unlessstated otherwise be substituted in one or more substitutable positionswith various groups, as described below.

The term “heteroaryl” refers to an aromatic ring system containing atleast one heteroatom selected from nitrogen, oxygen and sulfur in anaromatic ring. The heteroaryl may be fused to one or more cycloalkyl orheterocycloalkyl rings. Examples of heteroaryl groups include, forexample, pyridyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl,indolinyl, pyridazinyl, pyrazinyl, isoindolyl, isoquinolyl,quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl,pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl,thiadiazolyl, benzo[1,4]oxazinyl, triazolyl, tetrazolyl, isothiazolyl,naphthyridinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl,isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl,isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, pteridinyl,benzothiazolyl, imidazopyridinyl, imidazothiazolyl,dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, chromonyl,chromanonyl, pyridinyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl,dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl,dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl,pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinylN-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide,isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide,phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolylN-oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide,benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide,oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolylN-oxide, benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide.Preferred heteroaryl groups include pyridyl, pyrimidyl, quinolinyl,indolyl, pyrrolyl, furanyl, thienyl and imidazolyl, pyrazolyl,indazolyl, thiazolyl and benzothiazolyl. In certain embodiments, eachheteroaryl is selected from pyridyl, pyrimidinyl, pyridazinyl,pyrazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl,furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl,tetrazolyl, isothiazolyl, pyridinyl-N-oxide, pyrrolyl N-oxide,pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, imidazolylN-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide,pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolylN-oxide, and tetrazolyl N-oxide. Preferred heteroaryl groups includepyridyl, pyrimidyl, quinolinyl, indolyl, pyrrolyl, furanyl, thienyl,imidazolyl, pyrazolyl, indazolyl, thiazolyl and benzothiazolyl. Theheteroaryl groups herein are unsubstituted or, when specified as“optionally substituted”, can unless stated otherwise be substituted inone or more substitutable positions with various groups, as describedbelow.

The term “heterocycloalkyl” refers to a non-aromatic ring or ring systemcontaining at least one heteroatom that is preferably selected fromnitrogen, oxygen and sulfur, wherein said heteroatom is in anon-aromatic ring. The heterocycloalkyl may be saturated (i.e., aheterocycloalkyl) or partially unsaturated (i.e., a heterocycloalkenyl).The heterocycloalkyl ring is optionally fused to other heterocycloalkylrings and/or non-aromatic hydrocarbon rings and/or phenyl rings. Incertain embodiments, the heterocycloalkyl groups have from 3 to 7members in a single ring. In other embodiments, heterocycloalkyl groupshave 5 or 6 members in a single ring. Examples of heterocycloalkylgroups include, for example, azabicyclo[2.2.2]octyl (in each case also“quinuclidinyl” or a quinuclidine derivative), azabicyclo[3.2.1]octyl,morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinylS,S-dioxide, 2-oxazolidonyl, piperazinyl, homopiperazinyl,piperazinonyl, pyrrolidinyl, azepanyl, azetidinyl, pyrrolinyl,tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl,3,4-dihydroisoquinolin-2(1H)-yl, isoindolindionyl, homopiperidinyl,homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S,S-dioxide,oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl,dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl,imidazolidonyl, tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxideand homothiomorpholinyl S-oxide. Especially desirable heterocycloalkylgroups include morpholinyl, 3,4-dihydroisoquinolin-2(1H)-yl,tetrahydropyranyl, piperidinyl, aza-bicyclo[2.2.2]octyl,γ-butyrolactonyl (i.e., an oxo-substituted tetrahydrofuranyl),γ-butryolactamyl (i.e., an oxo-substituted pyrrolidine), pyrrolidinyl,piperazinyl, azepanyl, azetidinyl, thiomorpholinyl, thiomorpholinylS,S-dioxide, 2-oxazolidonyl, imidazolidonyl, isoindolindionyl,piperazinonyl. The heterocycloalkyl groups herein are unsubstituted or,when specified as “optionally substituted”, can unless stated otherwisebe substituted in one or more substitutable positions with variousgroups, as described below.

The term “cycloalkyl” refers to a non-aromatic carbocyclic ring or ringsystem, which may be saturated (i.e., a cycloalkyl) or partiallyunsaturated (i.e., a cycloalkenyl). The cycloalkyl ring optionally fusedto or otherwise attached (e.g., bridged systems) to other cycloalkylrings. Preferred cycloalkyl groups have from 3 to 7 members in a singlering. More preferred cycloalkyl groups have 5 or 6 members in a singlering. Examples of cycloalkyl groups include, for example, cyclohexyl,cyclopentyl, cyclobutyl, cyclopropyl, tetrahydronaphthyl andbicyclo[2.2.1]heptane. The cycloalkyl groups herein are unsubstitutedor, when specified as “optionally substituted”, may be substituted inone or more substitutable positions with various groups.

The term “oxa” means a divalent oxygen radical in a chain, sometimesdesignated as —O—.

The term “oxo” means a doubly bonded oxygen, sometimes designated as ═Oor for example in describing a carbonyl “C(O)” may be used to show anoxo substituted carbon.

The term “electron withdrawing group” means a group that withdrawselectron density from the structure to which it is attached than would asimilarly-attached hydrogen atom. For example, electron withdrawinggroups can be selected from the group consisting of halo, cyano, —(C₁-C₄fluoroalkyl), —O—(C₁-C₄ fluoroalkyl), —C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), —S(O)₂O—(C₀-C₄ alkyl), NO₂ and—C(O)—Hca in which the Hca includes a nitrogen atom to which the —C(O)—is bound, in which no alkyl, fluoroalkyl or heterocycloalkyl issubstituted with an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group.

The term “substituted,” when used to modify a specified group orradical, means that one or more hydrogen atoms of the specified group orradical are each, independently of one another, replaced with the sameor different substituent groups as defined below.

Substituent groups for substituting for hydrogens on saturated carbonatoms in the specified group or radical are, unless otherwise specified,—R⁶⁰, halo, —O⁻M⁺, ═O, —OR⁷⁰, —SR⁷⁰, —S⁻M⁺, ═S, —NR⁸⁰R⁸⁰, ═NR⁷⁰,═N—OR⁷⁰, trihalomethyl, —CF₃, —CN, —OCN, —SCN, —NO, —NO₂, —N₂, —N₃,—SO₂R⁷⁰, —SO₂O⁻M⁺, —SO₂OR⁷⁰, —OSO₂R⁷⁰, —OSO₂O⁻M⁺, —OSO₂OR⁷⁰,—P(O)(O⁻)₂(M⁺)₂, —P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂, —C(O)R⁷⁰, —C(S)R⁷⁰,—C(NR⁷⁰)R⁷⁰, —C(O)O⁻M⁺, —C(O)OR⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰,—C(NR⁷⁰)NR⁸⁰R⁸⁰, —OC(O)R⁷⁰, —OC(S)R⁷⁰, —OC(O)O⁻M⁺, —OC(O)OR⁷⁰,—OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂ ⁻M⁺, —NR⁷⁰CO₂R⁷⁰,—NR⁷⁰C(S)OR⁷⁰, —NR⁷⁰C(O)NR⁸⁰R⁸⁰, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and—NR⁷⁰C(NR⁷⁰)NR⁸⁰R⁸⁰. Each R⁶⁰ is independently selected from the groupconsisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl andheteroarylalkyl, each of which is optionally substituted with 1, 2, 3, 4or 5 groups selected from the group consisting of halo, —O⁻M⁺, ═O,—OR⁷¹, —SR⁷¹, —S⁻M⁺, ═S, —NR⁸¹R⁸¹, ═NR⁷¹, ═N—OR⁷¹, trihalomethyl, —CF₃,—CN, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —SO₂R⁷¹, —SO₂O⁻M⁺, —SO₂OR⁷¹,—OSO₂R⁷¹, —OSO₂O⁻M⁺, —OSO₂OR⁷¹, —P(O)(O⁻)₂(M⁺)₂, —P(O)(OR⁷¹)O⁻M⁺,—P(O)(OR⁷¹)₂, —C(O)R⁷¹, —C(S)R⁷¹, —C(NR⁷¹)R⁷¹, —C(O)O⁻M⁺, —C(O)OR⁷¹,—C(S)OR⁷¹, —C(O)NR⁸¹R⁸¹, —C(NR⁷¹)NR⁸¹R⁸¹, —OC(O)R⁷¹, —OC(S)R⁷¹,—OC(O)O⁻M⁺, —OC(O)OR⁷¹, —OC(O)OR⁷¹, —OC(S)OR⁷¹, —NR⁷¹C(O)R⁷¹,—NR⁷¹C(S)R⁷¹, —NR⁷¹CO₂ ⁻M⁺, —NR⁷¹CO₂R⁷¹, —NR⁷¹C(S)OR⁷¹,—NR⁷¹C(O)NR⁸¹R⁸¹, —NR⁷¹C(NR⁷¹)R⁷¹ and —NR⁷¹C(NR⁷¹)NR⁸¹R⁸¹. Each R⁷⁰ isindependently hydrogen or R⁶⁰; each R⁸⁰ is independently R⁷⁰ oralternatively, two R⁸⁰'s, taken together with the nitrogen atom to whichthey are bonded, form a 5-, 6- or 7-membered heterocycloalkyl which mayoptionally include from 1 to 4 of the same or different additionalheteroatoms selected from the group consisting of O, N and S, of which Nmay have —H or C₁-C₃ alkyl substitution; and each M⁺ is a counter ionwith a net single positive charge. Each R⁷¹ is independently hydrogen orR⁶¹, in which R⁶¹ is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl andheteroarylalkyl, each of which is optionally substituted with 1, 2, 3, 4or 5 groups selected from the group consisting of halo, —O⁻M⁺, ═O,—OR⁷², —SR⁷², —S⁻M⁺, ═S, —NR⁸²R⁸², ═NR⁷², ═N—OR⁷², trihalomethyl, —CF₃,—CN, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —SO₂R⁷¹, —SO₂O⁻M⁺, —SO₂OR⁷²,—OSO₂R⁷², —OSO₂O⁻M⁺, —OSO₂OR⁷², —P(O)(O⁻)₂(M⁺)₂, —P(O)(OR⁷²)O⁻M⁺,—P(O)(OR⁷²)₂, —C(O)R⁷², —C(S)R⁷², —C(NR⁷²)R⁷², —C(O)O⁻M⁺, —C(O)OR⁷²,—C(S)OR⁷², —C(O)NR⁸²R⁸², —C(NR⁷²)NR⁸²R⁸², —OC(O)R⁷², —OC(S)R⁷²,—OC(O)O⁻M⁺, —OC(O)OR⁷², —OC(S)OR⁷², —NR⁷²C(O)R⁷², —NR⁷²C(S)R⁷², —NR⁷²CO₂⁻M⁺, —NR⁷²CO₂R⁷², —NR⁷²C(S)OR⁷², —NR⁷²C(O)NR⁸²R⁸², —NR⁷²C(NR⁷²)R⁷² and—NR⁷²C(NR⁷²)NR⁸²R⁸²; and each R⁸¹ is independently R⁷¹ or alternatively,two R⁸¹s, taken together with the nitrogen atom to which they arebonded, form a 5-, 6- or 7-membered heterocycloalkyl which mayoptionally include from 1 to 4 of the same or different additionalheteroatoms selected from the group consisting of O, N and S, of which Nmay have —H or C₁-C₃ alkyl substitution. Each R⁷² is independentlyhydrogen, (C₁-C₆ alkyl) or (C₁-C₆ fluoroalkyl); each R⁸² isindependently R⁷² or alternatively, two R⁸²s, taken together with thenitrogen atom to which they are bonded, form a 5-, 6- or 7-memberedheterocycloalkyl which may optionally include 1, 2, 3 or 4 of the sameor different additional heteroatoms selected from the group consistingof O, N and S, of which N may have —H or C₁-C₃ alkyl substitution. EachM⁺ may independently be, for example, an alkali ion, such as K⁺, Na⁺,Li⁺; an ammonium ion, such as ⁺N(R⁶⁰)₄; or an alkaline earth ion, suchas [Ca²⁺]_(0.5), [Mg²⁺]_(0.5), or [Ba²⁺]_(0.5) (“subscript 0.5 meanse.g. that one of the counter ions for such divalent alkali earth ionscan be an ionized form of a presently disclosed compound and the other atypical counter ion such as chloride, or two ionized presently disclosedmolecules can serve as counter ions for such divalent alkali earth ions,or a doubly ionized compound can serve as the counter ion for suchdivalent alkali earth ions). As specific examples, —NR⁸⁰R⁸⁰ is meant toinclude —NH₂, —NH-alkyl, N-pyrrolidinyl, N-piperazinyl,4-methyl-piperazin-1-yl and N-morpholinyl.

Substituent groups for hydrogens on unsaturated carbon atoms in“substituted” alkene, alkyne, aryl and heteroaryl groups are, unlessotherwise specified, —R⁶⁰, halo, —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, —S⁻M⁺, —NR⁸⁰R⁸⁰,trihalomethyl, —CF₃, —CN, —OCN, —SCN, —NO, —NO₂, —N₃, —SO₂R⁷⁰, —SO₃ ⁻M⁺,—SO₃R⁷⁰, —OSO₂R⁷⁰, —OSO₃ ⁻M⁺, —OSO₃R⁷⁰, —PO₃ ⁻²(M⁺)₂, —P(O)(OR⁷⁰)O⁻M⁺,—P(O)(OR⁷⁰)₂, —C(O)R⁷⁰, —C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —CO₂ ⁻M⁺, —CO₂R⁷⁰,—C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰, —C(NR⁷⁰)NR⁸⁰R⁸⁰, —OC(O)R⁷⁰, —OC(S)R⁷⁰, —OCO₂⁻M⁺, —OCO₂R⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂ ⁻M⁺,—NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰, —NR⁷⁰C(O)NR⁸⁰R⁸⁰, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and—NR⁷⁰C(NR⁷⁰)NR⁸⁰R⁸⁰, where R⁶⁰, R⁷⁰, R⁸⁰ and M⁺ are as previouslydefined.

Substituent groups for hydrogens on nitrogen atoms in “substituted”heteroalkyl and heterocycloalkyl groups are, unless otherwise specified,—R⁶⁰, —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, —S⁻M⁺, —NR⁸⁰R⁸⁰, trihalomethyl, —CF₃, —CN,—NO, —NO₂, —S(O)₂R⁷⁰, —S(O)₂O⁻M⁺, —S(O)₂OR⁷⁰, —OS(O)₂R⁷⁰, —OS(O)₂O⁻M⁺,—OS(O)₂OR⁷⁰, —P(O)(O⁻)₂(M⁺)₂, —P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)(OR⁷⁰),—C(O)R⁷⁰, —C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —C(O)OR⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰,—C(NR⁷⁰)NR⁸⁰R⁸⁰, —OC(O)R⁷⁰, —OC(S)R⁷⁰, —OC(O)OR⁷⁰, —OC(S)OR⁷⁰,—NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰C(O)OR⁷⁰, —NR⁷⁰C(S)OR⁷⁰,—NR⁷⁰C(O)NR⁸⁰R⁸⁰, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)NR⁸⁰R⁸⁰, where R⁶⁰,R⁷⁰, R⁸⁰ and M⁺ are as previously defined.

In certain embodiments of the compounds disclosed herein, a group thatis substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents,1 or 2 substituents, or 1 substituent.

The compounds disclosed herein can also be provided as pharmaceuticallyacceptable salts. The term “pharmaceutically acceptable salts” or “apharmaceutically acceptable salt thereof” refer to salts prepared frompharmaceutically acceptable non-toxic acids or bases including inorganicacids and bases and organic acids and bases. If the compound is basic,salts may be prepared from pharmaceutically acceptable non-toxic acids.Such salts may be, for example, acid addition salts of at least one ofthe following acids: benzenesulfonic acid, citric acid, α-glucoheptonicacid, D-gluconic acid, glycolic acid, lactic acid, malic acid, malonicacid, mandelic acid, phosphoric acid, propanoic acid, succinic acid,sulfuric acid, tartaric acid (d, l, or dl), tosic acid (toluenesulfonicacid), valeric acid, palmitic acid, pamoic acid, sebacic acid, stearicacid, lauric acid, acetic acid, adipic acid, carbonic acid,4-chlorobenzenesulfonic acid, ethanedisulfonic acid, ethylsuccinic acid,fumaric acid, galactaric acid (mucic acid), D-glucuronic acid,2-oxo-glutaric acid, glycerophosphoric acid, hippuric acid, isethionicacid (ethanolsulfonic acid), lactobionic acid, maleic acid,1,5-naphthalene-disulfonic acid, 2-naphthalene-sulfonic acid, pivalicacid, terephthalic acid, thiocyanic acid, cholic acid, n-dodecylsulfate, 3-hydroxy-2-naphthoic acid, 1-hydroxy-2-naphthoic acid, oleicacid, undecylenic acid, ascorbic acid, (+)-camphoric acid,d-camphorsulfonic acid, dichloroacetic acid, ethanesulfonic acid, formicacid, hydriodic acid, hydrobromic acid, hydrochloric acid,methanesulfonic acid, nicotinic acid, nitric acid, orotic acid, oxalicacid, picric acid, L-pyroglutamic acid, saccharine, salicylic acid,gentisic acid, and/or 4-acetamidobenzoic acid.

The compounds described herein can also be provided in prodrug form.“Prodrug” refers to a derivative of an active compound (drug) thatrequires a transformation under the conditions of use, such as withinthe body, to release the active drug. Prodrugs are frequently, but notnecessarily, pharmacologically inactive until converted into the activedrug. Prodrugs are typically obtained by masking a functional group inthe drug believed to be in part required for activity with a progroup(defined below) to form a promoiety which undergoes a transformation,such as cleavage, under the specified conditions of use to release thefunctional group, and hence the active drug. The cleavage of thepromoiety can proceed spontaneously, such as by way of a hydrolysisreaction, or it can be catalyzed or induced by another agent, such as byan enzyme, by light, by acid, or by a change of or exposure to aphysical or environmental parameter, such as a change of temperature.The agent can be endogenous to the conditions of use, such as an enzymepresent in the cells to which the prodrug is administered or the acidicconditions of the stomach, or it can be supplied exogenously. A widevariety of progroups, as well as the resultant promoieties, suitable formasking functional groups in the active drugs to yield prodrugs arewell-known in the art. For example, a hydroxyl functional group can bemasked as a sulfonate, ester or carbonate promoiety, which can behydrolyzed in vivo to provide the hydroxyl group. An amino functionalgroup can be masked as an amide, carbamate, imine, urea, phosphenyl,phosphoryl or sulfenyl promoiety, which can be hydrolyzed in vivo toprovide the amino group. A carboxyl group can be masked as an ester(including silyl esters and thioesters), amide or hydrazide promoiety,which can be hydrolyzed in vivo to provide the carboxyl group. Otherspecific examples of suitable progroups and their respective promoietieswill be apparent to those of skill in the art.

The compounds disclosed herein can also be provided as N-oxides.

The presently disclosed compounds, salts, prodrugs and N-oxides can beprovided, for example, in solvate or hydrate form.

Compounds can be assayed for binding to a membrane-bound adiponectinreceptor by performing a competitive binding assay with adiponectin. Inone such procedure, HEK 293 cellular membrane is coated onto a COSTAR384 plate, which is then blocked with 1% casein. Polyhistidine-taggedglobular adiponectin and a candidate compound is incubated with themembrane in HEPES buffer. Unbound ligands are washed away and the degreeof binding of the adiponectin is determined using horseradishperoxidase-conjugated anti-polyhistidine. Compounds that compete withadiponectin binding to the membrane (i.e., give a reduced signalcompared to a control performed without a candidate compound) can bechosen as hits and further screened using the below-described functionalassays to identify adiponectin receptor agonists.

An in-cell western assay can be performed to demonstrate the activationof AMPK in human liver cells by globular adiponectin using glutathioneS-transferase (GST). AMPK activity can be measured by the relativeconcentration of phosphorylated acetyl Co-A carboxylase, which is one ofthe products of AMPK. An increase in pACC correlates with an increase inthe rate of fatty acid oxidation.

The compounds of structural formulae (I)-(LXIX) can be administered, forexample, orally, topically, parenterally, by inhalation or spray orrectally in dosage unit formulations containing one or morepharmaceutically acceptable carriers, diluents or excipients. The termparenteral as used herein includes percutaneous, subcutaneous,intravascular (e.g., intravenous), intramuscular, or intrathecalinjection or infusion techniques and the like.

Pharmaceutical compositions can be made using the presently disclosedcompounds. For example, in one embodiment, a pharmaceutical compositionincludes a pharmaceutically acceptable carrier, diluent or excipient,and compound as described above with reference to structural formulae(I)-(LXIX).

In the pharmaceutical compositions disclosed herein, one or morecompounds of structural formulae (I)-(LXIX) may be present inassociation with one or more pharmaceutically acceptable carriers,diluents or excipients, and, if desired, other active ingredients. Thepharmaceutical compositions containing compounds of structural formulae(I)-(LXIX) may be in a form suitable for oral use, for example, astablets, troches, lozenges, aqueous or oily suspensions, dispersiblepowders or granules, emulsion, hard or soft capsules, or syrups orelixirs.

Compositions intended for oral use can be prepared according to anysuitable method for the manufacture of pharmaceutical compositions andsuch compositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreservative agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients that aresuitable for the manufacture of tablets. These excipients can be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets can be uncoated or they can be coated by known techniques. Insome cases such coatings can be prepared by suitable techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate canbe employed.

Formulations for oral use can also be presented as hard gelatincapsules, wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil.

Formulations for oral use can also be presented as lozenges.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients can be suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents such as a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions can be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents and flavoring agents may beadded to provide palatable oral preparations. These compositions may bepreserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents orsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, can also be present.

Pharmaceutical compositions can also be in the form of oil-in-wateremulsions. The oily phase can be a vegetable oil or a mineral oil ormixtures of these. Suitable emulsifying agents can benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions can also containsweetening and flavoring agents.

Syrups and elixirs can be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol, glucose or sucrose. Suchformulations can also contain a demulcent, a preservative, flavoring,and coloring agents. The pharmaceutical compositions can be in the formof a sterile injectable aqueous or oleaginous suspension. Thissuspension can be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents that havebeen mentioned above. The sterile injectable preparation can also be asterile injectable solution or suspension in a non-toxic parentallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that can beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils can be employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid find use in the preparation of injectables.

Compounds of structural formulae (I)-(LXIX) can also be administered inthe form of suppositories, e.g., for rectal administration of the drug.These compositions can be prepared by mixing the compound with asuitable non-irritating excipient that is solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum to release the drug. Such materials include cocoa butter andpolyethylene glycols.

Compounds of structural formula (I)-(LXIX) can also be administeredparenterally in a sterile medium. The drug, depending on the vehicle andconcentration used, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

The compounds disclosed herein can be made using procedures familiar tothe person of ordinary skill in the art and as described herein. Forexample, compounds of structural formulae (II)-(III) can be preparedaccording to Scheme 1, below, or analogous synthetic schemes:

Referring to Scheme 1, BOC-protectedtetrahydro-1H-pyrido[4,3-b]indolecarboxylate ester 1, for example, isde-BOC'd and coupled with a benzaldehyde via e.g. reductive amination toform benzyl-substituted compound 2. The ester is saponified andprotonated to form the corresponding carboxylic acid 3, which is thencoupled with a suitable amine (in this case, a substituted1-benzylpiperidin-4-amine) to form Compound 4 of Table 1. Examples ofthe syntheses of compounds according to structural formula (III) areprovided below in Example 1.

Compounds of structural formulae (IV)-(V) can be prepared according toScheme 2, below, or analogous synthetic schemes:

Referring to Scheme 2, aldehydic acid 1, for example, can be coupledwith amine 2 to provide amide 3. Amide 3 in turn can be reductivelycoupled with piperazine 4 to provide compounds of structural formulae(IV) or (V). An example of the synthesis of a compound of structuralformula (IV) is provided below in Example 2.

Compounds of structural formulae (VI)-(VII) can be prepared according toScheme 3, below, or analogous synthetic schemes:

Referring to Scheme 3, hydroxynaphthoic acid 1, for example, is coupledwith a protected (e.g. benzyl) 4-aminopiperidine 2 to formN-piperidin-4-yl naphthamide 3, which is coupled with4-hydroxypiperidine 4, for example under Mitsunobu conditions, to formCompound 65 of Table 1. An example of the synthesis of a compound ofstructural formula (VI) is provided below in Example 3.

Compounds of structural formulae (VII)-(IX) can be prepared according toScheme 4, below, or analogous synthetic schemes:

Referring to Scheme 4, methoxyquinolinecarboxylic acid 1, for example,is converted to the corresponding hydroxyquinolinecarboxylic acid 2, byremoval of the methyl group with, e.g., boron tribromide. The acidmoiety is coupled with Boc-protected 4-aminopiperidine to form protectedN-piperidin-4-yl quinolinecarboxamide 3. Coupling of the hydroxyl groupof 3 with a desired 4-hydroxypiperidine yields Boc-protected compound 4,which is deprotected to yield the N-piperidin-4-ylpiperidinyloxyquinolinecarboxamide 5. Reductive amination of abenzaldehyde with the amide pipiridine yields Compound 69 of Table 1. Anexample of the synthesis of a compound of structural formula (IX) isprovided below in Example 4.

Compounds of structural formulae (X) -(XI) can be prepared according toScheme 5, below, or analogous synthetic schemes:

Referring to Scheme 5, methoxyindole ester 1, for example, is convertedto the corresponding hydroxyindole carboxylic acid 2 with borontribromide. Carboxylic acid 2 is coupled with Hca amine to yieldhydroxyindole amide 3. Hydroxyazacycloalkanol 4 (illustrated as a4-hydroxypiperidine) is coupled with amide 3 to yield(azacycloalkoxy)benzoindoleamide 5. An example of the synthesis of acompound of structural formula (X) is provided below in Example 5.

One of skill in the art can adapt the reaction sequences of Schemes 1-5to fit the desired target molecule. Of course, in certain situations oneof skill in the art will use different reagents to affect one or more ofthe individual steps or to use protected versions of certain of thesubstituents. Additionally, one skilled in the art would recognize thatcompounds of structural formulae (I)-(LXIX) can be synthesized usingdifferent routes altogether.

Compounds suitable for use in the presently disclosed pharmaceuticalcompositions include compounds of Table 1, above. These compounds can bemade according to the general schemes described above, for example usinga procedure similar to that described below in the Examples.

While not intending to be bound by theory, the inventors surmise thatcompounds of structural formulae (I)-(LXIX) are mimics of adiponectinwhich act as adiponectin receptor agonists, thereby activating the AMPKpathway. Activation of the AMPK pathway has the effect of increasingglucose uptake, decreasing glycogen synthesis and increasing fatty acidoxidation, thereby reducing glycogen, intracellular triglyceride andfatty acid concentration and causing an increase in insulin sensitivity.Because they activate the AMPK pathway, compounds of structural formulae(I)-(LXIX) should also inhibit the inflammatory processes which occurduring the early phases of atherosclerosis. Accordingly, compounds ofstructural formulae (I)-(LXIX) can be useful in the treatment of type IIdiabetes and in the treatment and prevention of atherosclerosis,cardiovascular disease, obesity and non-alcoholic fatty liver disease.

Accordingly, another aspect of the present disclosure relates to amethod of activating the AMPK pathway. According to this aspect, amethod for activating the AMPK pathway in a cell includes contacting thecell with an effective amount of a compound, pharmaceutically acceptablesalt, prodrug, N-oxide (or solvate or hydrate thereof) or compositiondescribed above.

In one embodiment, a method of increasing fatty acid oxidation in a cellincludes contacting the cell with an effective amount of a compound,pharmaceutically acceptable salt, prodrug, N-oxide (or solvate orhydrate thereof) or composition described above. Acetyl Co-A carboxylase(ACC) catalyzes the formation of malonyl Co-A, a potent inhibitor offatty acid oxidation; phosphorylation of ACC greatly reduces itscatalytic activity, thereby reducing the concentration of malonyl Co-Aand increasing the rate of fatty acid oxidation. Because the presentlydisclosed compounds can increase the rate of phosphorylation of ACC,they can reduce the inhibition of fatty acid oxidation and thereforeincrease its overall rate.

In another embodiment, a method of decreasing glycogen concentration ina cell includes contacting the cell with an effective amount of acompound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvateor hydrate thereof) or composition described above.

In another embodiment, a method of increasing glucose uptake in a cellincludes contacting the cell with an effective amount of a compound,pharmaceutically acceptable salt, prodrug, N-oxide (or solvate orhydrate thereof) or composition described above.

In another embodiment, a method of reducing triglyceride levels in asubject includes administering to the subject an effective amount of acompound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvateor hydrate thereof) or composition described above.

In another embodiment, a method of increasing insulin sensitivity of asubject includes administering to the subject an effective amount of acompound, pharmaceutically acceptable salt prodrug, N-oxide (or solvateor hydrate thereof) or composition described above.

Accordingly, the compounds and compositions disclosed herein can be usedto treat a variety of metabolic disorders. For example, in oneembodiment, a method of treating type II diabetes in a subject in needof such treatment includes administering to the subject an effectiveamount of a compound, pharmaceutically acceptable salt, prodrug,solvate, hydrate, N-oxide or composition described above. In anotherembodiment, a method of treating or preventing atherosclerosis orcardiovascular disease in a subject includes administering to thesubject an effective amount of a compound, pharmaceutically acceptablesalt, prodrug prodrug, N-oxide (or solvate or hydrate thereof) orcomposition described above.

As described above, the compounds disclosed herein can act as activatorsof the AMPK pathway. Accordingly, in another embodiment, a methodcomprises modulating the AMPK pathway (either in vitro or in vivo) bycontacting a cell with a compound, pharmaceutically acceptable salt,prodrug, N-oxide (or solvate or hydrate thereof) or compositiondescribed above, or administering a compound, pharmaceuticallyacceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) orcomposition described above to a mammal (e.g., a human) in an amountsufficient to modulate the AMPK activity and study the effects therebyinduced. Such methods are useful for studying the AMPK pathway and itsrole in biological mechanisms and disease states both in vitro and invivo.

Another embodiment is the use of a compound, pharmaceutically acceptablesalt, prodrug, N-oxide (or solvate or hydrate thereof) or composition asdescribed above in the manufacture of a medicament for any of thetherapeutic purposes described above. For example, the medicament can befor the reduction of triglyceride levels in a subject, the treatment oftype II diabetes in a subject, or the treatment or prevention ofatherosclerosis or cardiovasclular disease in a subject.

The compounds disclosed herein can be linked to labeling agents, forexample for use in variety of experiments exploring their receptorbinding, efficacy and metabolism. Accordingly, another embodiment is alabeled conjugate comprising a compound as disclosed herein covalentlylinked to a labeling agent, optionally through a linker. Suitable linkerand labeling agents will be readily apparent to those of skill in theart upon consideration of the present disclosure. The labeling agent canbe, for example, an affinity label such as biotin or strepavidin, ahapten such as digoxigenin, an enzyme such as a peroxidase, or afluorophoric or chromophoric tag. Any suitable linker can be used. Forexample, in some embodiments, an ethylene glycol, oligo(ethylene glycol)or poly(ethylene glycol) linker is used. Other examples of linkersinclude amino acids, which can be used alone or in combination withother linker groups, such as ethylene glycol, oligoethylene glycol orpolyethylene glycol. Suitable linkers include, without limitation,single amino acids, as well as di- and tripeptides. In one embodiment,the linker includes a glycine residue. The person of skill in the artwill realize, of course, that other linkers and labeling agents can beused. In other embodiments, an alkylene chain is the linker. In otherembodiments, the linker has the structure —[(C₀-C₃ alkyl)-Y^(m)—]_(m)—,in which each Y^(m) is —O—, —N(R⁹)—, or L, and m is in the range of1-40. For example, in certain embodiments, a labeled conjugate hasstructural formula (LXX):

in which the “LINK” moiety is a linker and is optional, and the “LABEL”moiety is a labeling agent, and all other variables are as describedabove, for example with reference to structural formula (I). Any of thecompounds disclosed with reference to structural formulae (I)-(LXIX) canbe used in the labeled conjugate of structural formula (LXX).

In certain embodiments, the -(LINK)₀₋₁-(LABEL) moiety is attached the“B” ring system at a benzo, pyrido or pyrazino ring position in the metaposition relative to the J moiety. For example, in one embodiment, alabeled conjugate has structural formula (LXXI):

in which the “LINK” moiety is a linker and is optional, and the “LABEL”moiety is a labeling agent, and all other variables are as describedabove, for example with reference to any of structural formulae (I),(II), (III), (XII), (XIII), (XXII)-(XXXIII) and (XLII)-(XLIX).

For example, in one particular embodiment, a labeled conjugate hasstructural formula (LXXII):

in which all variables are as described above, for example withreference to any of structural formulae (I), (II), (III), (XII), (XIII),(XXII)-(XXXIII) and (XLII)-(XLIX).

The following examples are intended to further illustrate certainembodiments and are not intended to limit the scope of the invention.

EXAMPLES Example 1 (a) Synthetic Example:2-benzyl-N-(1-(4-cyanobenzyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 4)

Compound 4 was prepared as described in Scheme 1, above.

Step 1

A solution of 2-tert-butyl 8-methyl3,4-dihydro-1H-pyrido[4,3-b]indole-2,8(5H)-dicarboxylate (0.5 g, 1.5mmol) in dichloromethane/trifluoroacetic acid (1:1, 10 mL) was stirredat room temperature for 1 h. The reaction mixture was then concentrated,diluted with acetic acid (5 mL) and concentrated again to give an oilyresidue. The residue was dissolved in THF/MeOH (4:1, 10 mL) followed bythe addition of benzaldehyde (170 μL, 180 mg, 1.7 mmol), sodiumtriacetoxyborohydride (485 mg, 2.3 mmol) and acetic acid (175 μL, 185mg, 3.1 mmol). Additional amounts of benzaldehyde (4×170 μL) and sodiumtriacetoxyborohydride (4×485 mg) were added over the course of theensuing 8 h. The resulting reaction mixture was stirred at roomtemperature overnight then poured over saturated sodium bicarbonatesolution (30 mL). The aqueous layer was then extracted withdichloromethane (3×30 mL) and the combined organic layer was washed withwater (2×30 mL), dried over MgSO₄, filtered and concentrated. Columnchromatography (neat dichloromethane→3% MeOH/CH₂Cl₂) provided methyl2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate as awhite crystalline solid (320 mg, 66%). ¹H NMR (CD₃OD): δ 8.17 (1H, d,J=1.1 Hz); 7.73 (1H, dd, J=8.7, 1.8 Hz); 7.44-7.27 (6H, m); 3.88 (3H,s); 3.83 (2H, br s); 3.73 (2H, br s) 2.95-2.88 (4H, m). MS (M+H)⁺=321.

Step 2

To a solution of methyl2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate (307mg, 1.0 mmol) in THF/MeOH/H₂O (2:1:1, 12 mL) was added lithium hydroxidemonohydrate (240 mg, 5.7 mmol). The reaction mixture was then allowed tostir at room temperature until all the starting material was consumed(2-3 days). The resulting cloudy reaction mixture was then concentratedto give a yellow foamy residue. Trituration with 10% HCl solutionprovided 2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylicacid as a yellow crystalline solid upon filtration and drying undervacuuo (269 mg, 92%). ¹H NMR (DMSO-d₆): δ 11.59 (1H, s); 10.92 (1H, s);8.07 (1H, s); 7.71 (1H, d, J=8.5 Hz); 7.65 (2H, d, J=3.6 Hz); 7.49 (3H,d, J=3.6 Hz); 7.39 (1H, d, J=8.5 Hz); 4.58-4.3 (4H, m); 3.78-3.69 (1H,m); 3.52-3.05 (3H, m). MS (M+H)⁺=307.

Step 3

To a solution of2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylic acid (50mg, 0.2 mmol) in DMF (2 mL), HATU(O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate) (75 mg, 0.2 mmol),4-amino-1-(4-cyanobenzyl)piperidine dihydrochloride (47 mg, 0.2 mmol)and triethylamine (105 μL, 76 mg, 0.8 mmol) were added. The resultingreaction mixture was stirred at room temperature overnight. The reactionmixture was poured into saturated sodium bicarbonate solution (30 mL) togive a white precipitate which was filtered and dried under vacuuo. Theresulting solid was triturated with ethyl ether to yield Compound 4 as awhite crystalline solid (80 mg, 97%). ¹H NMR (DMSO-d₆): δ 11.00 (1H, brs); 8.00 (1H, d, J=7.7 Hz); 7.82 (1H, s); 7.78 (2H, d, J=8.3 Hz); 7.53(1H, d, J=11.8 Hz); 7.50 (2H, d, J=7.7 Hz); 7.39 (2H, d, J=6.6 Hz); 7.36(2H, d, J=8.3 Hz); 7.32-7.23 (2H, m); 3.76 (3H, br s); 3.58 (4H, d,J=10.5 Hz); 2.89-2.73 (6H, m); 2.06 (2H, t, J=11.0 Hz); 1.76 (2H, d,J=9.9 Hz); 1.58 (2H, q, J=10.7 Hz). MS (M+H)⁺=504.

(b) Synthetic Example:N-(1-(4-Cyanobenzyl)piperidin-4-yl)-2-(4-(trifluoromethyl)phenylsulfonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 24)

Compound 24 was prepared according to Scheme 1(b), below:

Step 1

A solution of benzyl 4-oxo-1-piperidine carboxylate (1 in Scheme 1(b)),30.7 g, 131 mmol) and 4-hydrazinobenzoic acid (2, 20 g, 131 mmol) inACN/10% sulfuric acid (1:1, 400 mL) was allowed to stir at reflux for 19h. The reaction mixture was then cooled down to room temperature, andthe resulting yellow solid was collected by filtration, washed with H₂O(3×50 mL) and dried under vacuum overnight to provide2-(benzyloxycarbonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylicacid (3) as a pale yellow solid (35.2 g, 77%). ¹H NMR (DMSO-d₆, 300 MHZ)12.33 (br s, 1H), 11.30 (s, 1H), 8.06 (s, 1H), 7.66 (d, J=8.3 Hz, 1H),7.38-7.32 (m, 6H), 5.14 (s, 2H), 4.72-4.58 (m, 2H), 3.79 (br s, 2H),2.82 (br s, 2H) ppm; MS (ES) 351 (M+H).

Step 2

To a solution of2-(benzyloxycarbonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylicacid (3, 0.5 g, 1.4 mmol) in DMF (10 mL), HATU (0.65 g, 1.7 mmol),4-amino-1-(4-cyanobenzyl)piperidine dihydrochloride (0.41 g, 1.4 mmol)and triethylamine (1.05 mL, 0.76 g, 7.5 mmol) were added. The resultingreaction mixture was allowed to stir at room temperature overnight,poured into saturated sodium bicarbonate solution (75 mL) and extractedwith EtOAc (3×50 mL). The combined organic layers were washed with water(2×30 mL), brine (1×30 mL), dried (MgSO₄), filtered and concentrated togive a tan solid. Column chromatography (neat DCM→5% MeOH/DCM) providedbenzyl8-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(4a in Scheme 1(b)) as a white solid upon trituration with ethyl ether(0.55 g, 70%). ¹H NMR (DMSO-d₆, 300 MHZ) 11.14 (br s, 1H), 8.04 (d,J=8.0 Hz, 1H), 8.00 (s, 1H), 7.79 (d, J=8.0 Hz, 2H), 7.59 (d, J=8.5 Hz,1H), 7.51 (d, J=7.7 Hz, 2H), 7.39-7.27 (m, 6H), 5.14 (s, 2H), 4.67 (brs, 2H), 3.80 (br s, 3H), 3.57 (s, 2H), 2.82 (br s, 4H), 2.08 (t, J=11.0Hz, 2H), 1.80 (d, J=11.3 Hz, 2H), 1.61 (q, J=10.7 Hz, 2H) ppm; MS (ES)548 (M+H).

Step 3

To a solution of benzyl8-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(4a, 50 mg, 91 μmol) in DCM (dichloromethane) (1.0 mL) was addeddropwise a solution of HBr/AcOH (48% w/v, 1.0 mL). After the resultingbrown reaction mixture was stirred for 30 min, the volatiles wereevaporated, MeOH (2 mL) was added and the volatiles evaporated again.The resulting brown residue was dissolved in DMF (1.0 mL) andtriethylamine (0.5 mL, 0.36 g, 3.6 mmol) and4-(trifluoromethyl)benzenesulfonyl chloride (45 mg, 0.2 mmol) wereadded. The resulting reaction mixture was allowed to stir at roomtemperature overnight, then poured into saturated sodium bicarbonatesolution (20 mL) to give a brown precipitate which was filtered andpurified by reverse phase HPLC to provide Compound 24 upon triturationwith ethyl ether (18 mg, 31%). ¹H NMR (DMSO-d₆, 300 MHZ) 11.21 (br s,1H), 11.18 (br s, 1H), 9.75 (br s, 1H), 8.26 (d, J=7.2 Hz, 1H), 8.07 (d,J=8.3 Hz, 2H), 7.98 (d, J=7.7 Hz, 4H), 7.71 (d, J=8.3 Hz, 2H), 7.57 (d,J=8.5 Hz, 1H), 7.28 (d, J=8.5 Hz, 1H), 4.40 (d, J=8.3 Hz, 4H), 3.55-3.06(m, 7H), 2.92-2.82 (m, 2H), 2.07 (d, J=10.5 Hz, 2H), 1.78 (q, J=11.3 Hz,2H) ppm; MS (ES) 622 (M+H).

The following compounds were prepared using methods analogous to thosedescribed in Synthetic Example 1(b) and in Scheme 1(b).

Compound 19:N-(1-benzylpiperidin-4-yl)-2-(4-(trifluoromethyl)phenylsulfonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamidetrifluoroacetate (41%). ¹H NMR (CD₃OD, 300 MHz) 8.34 (d, J=7.2 Hz, 1H),8.04 (d, J=8.0 Hz, 2H), 7.93 (br s, 1H), 7.84 (d, J=8.3 Hz, 2H), 7.58(d, J=8.5 Hz, 1H), 7.52 (s, 5H), 7.29 (d, J=8.3 Hz, 1H), 4.48 (s, 2H),4.35 (s, 2H), 4.22-4.08 (m, 1H), 3.65-3.56 (m, 4H), 3.21 (t, J=11.6 Hz,2H), 2.90-2.82 (m, 2H), 2.28 (d, J=13.2 Hz, 2H), 1.90 (q, J=11.6 Hz, 2H)ppm; MS (ES) 597 (M+H).

Compound 25:N-(1-(4-cyanobenzyl)piperidin-4-yl)-2-(4-cyanophenylsulfonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamidetrifluoroacetate (13%). ¹H NMR (CD₃OD, 300 MHz) 8.01 (d, J=8.5 Hz, 2H),7.93 (d, J=1.1 Hz, 1H), 7.88 (d, J=8.8 Hz, 2H), 7.71 (d, J=8.3 Hz, 2H),7.59-7.55 (m, 3H), 7.29 (d, J=8.5 Hz; 1H), 4.49 (s, 2H), 4.00-3.88 (m,1H), 3.68 (s, 2H), 3.64 (t, J=5.9 Hz, 2H), 2.97 (d, J=11.8 Hz, 2H),2.85-2.82 (m, 2H), 2.28 (t, J=11.8 Hz, 2H), 1.99 (d, J=9.4 Hz, 2H), 1.75(q, J=11.8 Hz, 2H) ppm; MS (ES) 579 (M+H).

Compound 26:N-(1-(4-cyanobenzyl)piperidin-4-yl)-2-(pyridin-3-ylsulfonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamidetrifluoroacetate (24%). ¹H NMR (CD₃OD, 300 MHz) 8.98 (d, J=1.9 Hz, 1H),8.73 (dd, J=4.7, 1.7 Hz, 1H), 8.36-8.00 (m, 1H), 8.25 (ddd, J=8.3, 2.2,1.7 Hz, 1H), 7.95 (s, 1H), 7.89 (d, J=8.3 Hz, 2H), 7.71 (d, J=8.6 Hz,2H), 7.60-7.54 (m, 2H), 7.29 (d, J=8.3 Hz, 1H), 4.52 (br s, 2H), 4.43(br s, 2H), 4.23-4.10 (m, 1H), 3.67 (t, J=5.8 Hz, 2H), 3.61-3.52 (m,2H), 3.25-3.15 (m, 2H), 2.90-2.81 (m, 2H), 2.32-2.22 (m, 2H), 1.98-1.81(m, 2H) ppm; MS (ES) 555 (M+H).

(c) Synthetic Example:N-(1-(4-Cyanophenylsulfonyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyridor-4,3-blindole-8-carboxamide(Compound 21)

Compound 21 was prepared according to Scheme 1(c), below:

Step 1

Benzyl8-(1-(tert-butoxycarbonyl)piperidin-4-ylcarbamoyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(8 in Scheme 1(c)) was prepared as described in step 2 of SyntheticExample 1(b) above as an off-white solid (95%). ¹H NMR (DMSO-d₆, 300MHZ) 11.15 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.98 (br s, 1H), 7.59 (d,J=8.8 Hz, 1H), 7.38-7.27 (m, 6H), 5.14 (s, 2H), 4.66 (br s, 2H),4.06-3.88 (m, 3H), 3.80 (br s, 2H), 2.87-2.77 (m, 4H), 1.84-1.72 (m,2H), 1.52-1.35 (m, 11H) ppm; MS (ES) 533 (M+H).

Step 2

i) A solution of benzyl8-(1-(tert-butoxycarbonyl)piperidin-4-ylcarbamoyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(8, 20.98 g, 39 mmol) and Pd/C (10% wt.) (4.0 g) in MeOH (300 mL) wasallowed to stir at room temperature overnight. The palladium was thenfiltered, washed with MeOH and the resulting clear solution wasconcentrated to give tert-butyl4-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylateas a white foamy residue (11.63 g, 74%) ppm; MS (ES) 399 (M+H).

ii) To a solution of tert-butyl4-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate(11.63 g, 29.2 mmol) and 4-(trifluoromethyl)benzaldehyde (4.8 mL, 6.12g, 35.1 mmol) in DCM (200 mL), sodium triacetoxyborohydride (12.4 g, 8.5mmol) was added. The reaction mixture was allowed to stir at roomtemperature overnight and then poured into saturated sodium bicarbonatesolution (300 mL). The layers were separated, and the aqueous layer wasextracted with DCM (3×100 mL). The combined organic layers were washedwith brine (2×50 mL), dried (MgSO₄), filtered and concentrated to givean off-white solid. Trituration with ethyl ether provided tert-butyl4-(2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate(9 in Scheme 1(c)) as a white solid (13.60 g, 84%). ¹H NMR (DMSO-d₆, 300MHZ) 11.03 (br s, 1H), 8.01 (d, J=7.7 Hz, 1H), 7.83 (s, 1H), 7.71 (d,J=8.3 Hz, 2H), 7.62 (d, J=7.7 Hz, 2H), 7.55 (d, J=8.8 Hz, 1H), 7.26 (d,J=8.5 Hz, 1H), 4.22-3.83 (m, 5H), 3.62 (s, 2H), 2.90-2.77 (br s, 6H),1.82-1.70 (m, 2H), 1.55-1.30 (m, 11H) ppm; MS (ES) 557 (M+H)

Step 3

To a solution of tert-butyl4-(2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate(9, 50 mg, 90 μmol) in DCM (1.0 mL), TFA (1.0 mL) was added. Afterallowing the reaction mixture to stir at room temperature for 2 h, thevolatiles were evaporated, DCM and toluene (10 mL) were added and thevolatiles evaporated (2×). The resulting residue was dissolved in DMF(2.0 mL) and triethylamine (0.5 mL, 0.36 g, 3.6 mmol) and4-cyanobenzenesulfonyl chloride (22 mg, 110 μmol) were added. Theresulting reaction mixture was allowed to stir at room temperatureovernight, poured into saturated sodium bicarbonate solution (20 mL) togive a tan solid which was triturated with ethyl ether to provideN-(1-(4-cyanophenylsulfonyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 21, 54 mg, 97%). ¹H NMR (DMSO-d₆, 300 MHZ) 11.04 (br s, 1H),8.12 (d, J=8.5 Hz, 2H), 8.04 (d, J=7.7 Hz, 1H), 7.92 (d, J=8.3 Hz, 2H),7.79 (s, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.62 (d, J=7.7 Hz, 2H), 7.51 (d,J=8.5 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 3.86 (s, 2H), 3.82-3.72 (m, 1H),3.70-3.59 (m, 4H), 2.90-2.78 (m, 4H), 2.56-2.44 (m, 2H), 1.90-1.80 (m,2H), 1.64-1.48 (m, 2H) ppm; MS (ES) 622 (M+H).

The following compounds were prepared using methods analogous to thosedescribed in Synthetic Example 1(c) and in Scheme 1(c).

Compound 22:N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(93%). ¹H NMR (CD₃OD, 300 MHz) 8.94-8.93 (m, 1H), 8.82 (dd, J=4.8, 1.5Hz, 1H), 8.21 (ddd, J=8.0, 2.3, 1.5 Hz, 1H), 7.83-7.79 (m, 1H),7.69-7.61 (m, 5H), 7.53 (dd, J=8.5, 1.7 Hz, 1H), 7.28 (d, J=8.5 Hz, 1H),3.90-3.83 (m, 5H), 3.72 (s, 2H), 2.95-2.93 (m, 4H), 2.56 (t, J=12.0 Hz,2H), 2.06-1.96 (m, 2H), 1.78-1.62 (m, 2H) ppm; MS (ES) 598 (M+H).

Compound 23:2-(4-(trifluoromethyl)benzyl)-N-(1-(4-(trifluoromethyl)phenylsulfonyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(97%). ¹H NMR (DMSO-d₆, 300 MHZ) 11.03 (br s, 1H), 8.06 (s, 1H), 8.02(d, J=8.0 Hz, 2H), 7.96 (d, J=8.3 Hz, 2H), 7.79 (s, 1H), 7.71 (d, J=8.3Hz, 2H), 7.62 (d, J=8.0 Hz, 2H), 7.51 (d, J=8.5 Hz, 1H), 7.25 (d, J=8.5Hz, 1H), 3.86 (s, 2H), 3.82-3.74 (m, 1H), 3.67 (d, J=11.6 Hz, 2H), 3.61(s, 2H), 2.90-2.78 (m, 4H), 2.54-2.47 (m, 2H), 1.92-1.82 (m, 2H), 1.51(q, J=11.4 Hz, 2H) ppm; MS (ES) 665 (M+H).

Compound 28:N-(1-(4-fluorophenylsulfonyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(10d) (79%). ¹H NMR (DMSO-d₆, 300 MHZ) 11.03 (br s, 1H), 7.83-7.79 (m,4H), 7.71 (d, J=8.0 Hz, 2H), 7.62 (d, J=8.3 Hz, 2H), 7.53-7.45 (m, 3H),7.25 (d, J=8.5 Hz, 1H), 3.86 (s, 2H), 3.80-3.70 (m, 1H), 3.68-3.55 (m,4H), 2.84 (br s, 4H), 2.41 (t, J=10.9 Hz, 2H), 1.90-1.80 (m, 2H),1.66-1.50 (m, 2H) ppm; MS (ES) 615 (M+H).

Compound 29:N-(1-(3-cyanophenylsulfonyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(81%). ¹H NMR (DMSO-d₆, 300 MHZ) 11.03 (br s, 1H), 8.19 (d, J=8.8 Hz,2H), 8.07-8.03 (m, 2H), 7.84 (t, J=7.7 Hz, 1H), 7.79 (s, 1H), 7.71 (d,J=8.3 Hz, 2H), 7.62 (d, J=8.3 Hz, 2H), 7.51 (dd, J=8.5, 1.7 Hz, 1H),7.25 (d, J=8.5 Hz, 1H), 3.86 (s, 2H), 3.82-3.72 (m, 1H), 3.67 (d, J=11.6Hz, 2H), 3.62 (s, 2H), 2.84 (br s, 4H), 2.53-2.46 (m, 2H), 1.92-1.82 (m,2H), 1.65-1.50 (m, 2H) ppm; MS (ES) 622 (M+H).

Compound 30:2-(4-(trifluoromethyl)benzyl)-N-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(75%). ¹H NMR (DMSO-d₆, 300 MHZ) 11.04 (br s, 1H), 8.11 (d, J=7.4 Hz,1H), 8.06 (dd, J=7.2, 6.1 Hz, 2H), 7.96 (s, 1H), 7.90 (t, J=7.7 Hz, 1H),7.79 (s, 1H), 7.71 (d, J=8.3 Hz, 2H), 7.62 (d, J=8.0 Hz, 2H), 7.51 (dd,J=8.5, 1.4 Hz, 1H), 7.24 (d, J=8.3 Hz, 1H), 3.86 (s, 2H), 3.82-3.72 (m,1H), 3.68 (d, J=11.6 Hz, 2H), 3.61 (s, 2H), 2.84 (br s, 4H), 2.51-2.45(m, 2H), 1.92-1.82 (m, 2H), 1.66-1.52 (m, 2H) ppm; MS (ES) 665 (M+H).

Compound 32:N-(1-(4-chlorophenylsulfonyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamidetrifluoroacetate (59%). ¹H NMR (DMSO-d₆, 300 MHZ) 11.45 (br s, 1H),10.41 (br s, 1H), 8.12 (d, J=7.4 Hz, 1H), 7.91 (d, J=10.5 Hz, 3H), 7.82(d, J=6.9 Hz, 2H), 7.76 (d, J=8.8 Hz, 2H), 7.72 (d, J=9.1 Hz, 2H), 7.59(d, J=8.5 Hz, 1H), 7.35 (d, J=8.5 Hz, 1H), 4.67 (br s, 2H), 4.54-4.32(m, 2H), 3.77 (br s, 2H), 3.65 (d, J=11.6 Hz, 2H), 3.60-3.50 (m, 1H),3.13 (br s, 2H), 2.44 (t, J=10.7 Hz, 2H), 1.92-1.81 (m, 2H), 1.66-1.50(m, 2H) ppm; MS (ES) 631 (M+H).

(d) Synthetic Example:N-(1-nicotinoylpiperidin-4-yl)-2-(4-trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 42)

N-(1-Nicotinoylpiperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(compound 42) was prepared as described in step 3 of Synthetic Example1(c) above (using nicotinyl chloride hydrochloride instead of sulfonylchlorides) as an off-white solid (87%). ¹H NMR (DMSO-d₆, 300 MHZ) 11.05(s, 1H), 8.64 (dd, J=5.0, 1.7 Hz, 1H), 8.57 (d, J=1.9 Hz, 1H), 8.07 (d,J=7.7 Hz, 1H), 7.84 (s, 1H), 7.80 (dt, J=8.0, 1.9 Hz, 1H), 7.71 (d,J=8.3 Hz, 2H), 7.62 (d, J=8.0 Hz, 2H), 7.55 (dd, J=8.5, 1.7 Hz, 1H),7.48 (ddd, J=7.7, 5.0, 0.8 Hz, 1H), 7.26 (d, J=8.5 Hz, 1H), 4.45 (d,J=11.0 Hz, 1H), 4.14-4.00 (m, 1H), 3.86 (s, 2H), 3.62 (s, 2H), 3.60-3.50(m, 1H), 3.27-3.14 (m, 1H), 3.02-2.78 (m, 5H), 1.97-1.73 (m, 2H),1.62-1.40 (m, 2H) ppm; MS (ES) 562 (M+H).

(e) Synthetic Example:N-(1-(Pyridin-4-ylmethyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 50)

Step 1

A solution of tert-butyl4-(2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate(9 in Scheme 1(c)), 340 mg, 0.6 mmol) in 4 N HCl/dioxane (10.0 mL) wasallowed to stir at room temperature for 2 h. The reaction mixture wasthen concentrated and the resulting residue was triturated with ethylether to give4-(2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidinedihydrochloride salt as a white solid (320 mg, 100%).

Step 2

A solution of the dihydrochloride salt of step 1, above (65 mg, 0.12mmol) was dissolved in DMF (2.0 mL) and 4-(bromomethyl)pyridinehydrobromide (2×35 mg, 2×0.14 mmol) and triethylamine (2×80 μL, 2×58 mg,2×570 μmol) were added. The resulting reaction mixture was allowed tostir at room temperature overnight, poured into saturated sodiumbicarbonate solution (20 mL) to give an off-white solid which wastriturated with ethyl ether to provideN-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 50, 60%). ¹H NMR (DMSO-d₆, 300 MHZ) 11.02 (s, 1H), 8.49 (d,J=4.7 Hz, 2H), 7.99 (d, J=8.0 Hz, 1H), 7.84 (s, 1H), 7.71 (d, J=8.0 Hz,2H), 7.62 (d, J=8.3 Hz, 2H), 7.55 (d, J=8.3 Hz, 1H), 7.31 (d, J=4.7 Hz,2H), 7.25 (d, J=8.3 Hz, 1H), 3.86 (s, 2H), 3.82-3.70 (m, 1H), 3.63 (s,2H), 3.50 (s, 2H), 2.90-2.74 (m, 6H), 2.06 (t, J=11.1 Hz, 2H), 1.77 (d,J=10.2 Hz, 2H), 1.60 (q, J=10.9 Hz, 2H) ppm; MS (ES) 548 (M+H).

The following compounds were prepared as described in Synthetic Example1(e) and in Scheme 1(c).

Compound 51:N-(1-isonicotinoylpiperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(67%). ¹H NMR (DMSO-d₆, 300 MHZ) 11.04 (s, 1H), 8.66 (d, J=4.7 Hz, 2H),8.06 (d, J=7.4 Hz, 1H), 7.84 (s, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.62 (d,J=8.3 Hz, 2H), 7.55 (d, J=8.5 Hz, 1H), 7.35 (d, J=4.7 Hz, 2H), 7.26 (d,J=8.5 Hz, 1H), 4.44 (d, J=12.9 Hz, 1H), 4.15-4.00 (m, 1H), 3.87 (s, 2H),3.63 (s, 2H), 3.46 (d, J=12.9 Hz, 1H), 3.18 (t, J=12.4 Hz, 1H), 2.95 (t,J=12.4 Hz, 1H), 2.85 (br s, 4H), 1.92 (d, J=11.3 Hz, 1H), 1.78 (d,J=11.0 Hz, 1H), 1.57-1.44 (m, 2H) ppm; MS (ES) 562 (M+H).

Compound 52:N-(1-(4-carbamoylbenzyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(66%). ¹H NMR (DMSO-d₆, 300 MHZ) 11.02 (s, 1H), 7.99 (d, J=7.4 Hz, 1H),7.91 (s, 1H), 7.83 (s, 1H), 7.81 (d, J=8.8 Hz, 2H), 7.71 (d, J=8.0 Hz,2H), 7.62 (d, J=8.0 Hz, 2H), 7.54 (d, J=8.5 Hz, 1H), 7.35 (d, J=7.7 Hz,2H), 7.30 (s, 1H), 7.25 (d, J=8.5 Hz, 1H), 3.86 (s, 2H), 3.80-3.68 (m,1H), 3.63 (s, 2H), 3.51 (s, 2H), 2.90-2.76 (m, 6H), 2.03 (t, J=11.1 Hz,2H), 1.76 (d, J=10.2 Hz, 2H), 1.58 (q, J=10.6 Hz, 2H) ppm; MS (ES) 590(M+H).

(f) Synthetic Example:N-(1-((1-methyl-1H-imidazol-4-yl)methyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide.(Compound 53)

To a solution of the dihydrochloride salt prepared in step 1 ofSynthetic Example 1(e) (65 mg, 0.12 mmol) was dissolved in DCM (2.0 mL),1-methyl-1H-imidazole-4-carbaldehyde (2×16 mg, 2×0.15 mmol) and sodiumtriacetoxyborohydride (2×55 mg, 3×260 μmol) were added. The resultingreaction mixture was allowed to stir at room temperature overnight, andupon reaction completion, was poured into saturated sodium bicarbonatesolution (30 mL). The layers were separated, extracted aqueous layerwith EtOAc (3×20 mL), washed combined organic layer with brine (2×10mL), dried (MgSO₄), filtered and concentrated. Trituration of theresidue with ethyl ether providedN-(1-((1-methyl-1H-imidazol-4-yl)methyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamideas a white solid (Compound 53, 31 mg, 46%). ¹H NMR (DMSO-d₆, 300 MHZ)11.02 (s, 1H), 7.98 (d, J=7.4 Hz, 1H), 7.82 (s, 1H), 7.71 (d, J=8.0 Hz,2H), 7.62 (d, J=7.7 Hz, 2H), 7.54 (d, J=8.5 Hz, 1H), 7.44 (s, 1H), 7.25(d, J=8.5 Hz, 1H), 6.92 (s, 1H), 3.86 (s, 2H), 3.78-3.66 (m, 1H), 3.63(s, 2H), 3.60 (s, 3H), 3.30 (s, 2H), 2.92-2.78 (m, 6H), 1.98 (t, J=11.3Hz, 2H), 1.73 (d, J=11.0 Hz, 2H), 1.52 (q, J=10.8 Hz, 2H) ppm; MS (ES)551 (M+H).

The following compounds were prepared as described in Synthetic Example1(f) and in Scheme 1(c).

Compound 54:N-(1-(oxazol-4-ylmethyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(46%). ¹H NMR (DMSO-d₆, 300 MHZ) 11.02 (s, 1H), 8.28 (s, 1H), 7.99 (d,J=8.0 Hz, 1H), 7.95 (s, 1H), 7.82 (s, 1H), 7.70 (d, J=8.3 Hz, 2H), 7.62(d, J=8.0 Hz, 2H), 7.54 (d, J=8.5 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 3.86(s, 2H), 3.78-3.66 (m, 1H), 3.62 (s, 2H), 3.39 (s, 2H), 2.90-2.76 (m,6H), 2.04 (t, J=11.0 Hz, 2H), 1.75 (d, J=10.7 Hz, 2H), 1.54 (q, J=10.9Hz, 2H) ppm; MS (ES) 538 (M+H).

(g) Synthetic Example: N-Carbamoyl Compounds 27, 31, 33

Compound 27 was prepared as shown in Scheme 1(g)

N-(1-(4-cyanophenylcarbamoyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 27) was prepared as described in step 3 of Synthetic Example1(c), with purification by column chromatography (5%→10% MeOH/DCM) toyield the title compound as an off-white solid (37%). ¹H NMR (CD₃OD, 300MHz) 7.85 (d, J=1.4 Hz, 1H), 7.68-7.59 (m, 8H), 7.56 (d, J=1.7 Hz, 1H),7.30 (d, J=8.5 Hz, 1H), 4.23 (d, J=13.5 Hz, 2H), 4.16-4.08 (m, 1H), 3.90(s, 2H), 3.73 (s, 2H), 3.07 (t, J=12.0 Hz, 2H), 2.96-2.93 (m, 4H), 2.02(d, J=10.2 Hz, 2H), 1.67-1.55 (m, 2H) ppm; MS (ES) 601 (M+H).

2-(4-(Trifluoromethyl)benzyl)-N-(1-(4-(trifluoromethyl)phenylcarbamoyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamidetrifluoroacetate (Compound 33) was prepared as described in step 3 ofSynthetic Example 1(c) above followed by purification using HPLC as ayellow solid (60%). ¹H NMR (DMSO-d₆, 300 MHZ) 11.46 (s, 1H), 10.46 (brs, 1H), 8.95 (s, 1H), 8.12 (d, J=8.0 Hz, 1H), 7.97 (s, 1H), 7.90 (d,J=7.7 Hz, 2H), 7.81 (d, J=8.0 Hz, 2H), 7.70-7.63 (m, 3H), 7.57 (d, J=8.5Hz, 2H), 7.36 (d, J=8.5 Hz, 1H), 4.67 (br s, 2H), 4.58-4.33 (m, 2H),4.15 (d, J=12.7 Hz, 2H), 4.10-3.98 (m, 1H), 3.78 (br s, 2H), 3.14 (br s,2H), 2.95 (t, J=12.1 Hz, 2H), 1.84 (d, J=10.5 Hz, 2H), 1.56-1.45 (m, 2H)ppm; MS (ES) 644 (M+H).

N-(1-(4-Fluorophenylcarbamoyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamidewas prepared as described in step 3 of Synthetic Example 1(c) above asan off-white solid (96%). ¹H NMR (DMSO-d₆, 300 MHZ) 11.04 (s, 1H), 8.55(s, 1H), 8.05 (d, J=7.7 Hz, 1H), 7.84 (s, 1H), 7.70 (d, J=8.3 Hz, 2H),7.61 (d, J=8.0 Hz, 2H), 7.56 (dd, J=8.5, 1.7 Hz, 1H), 7.47-7.43 (m, 2H),7.26 (d, J=8.5 Hz, 1H), 7.05 (t, J=8.8 Hz, 2H), 4.11 (d, J=13.2 Hz, 2H),4.06-3.96 (m, 1H), 3.86 (s, 2H), 3.62 (s, 2H), 2.94-2.78 (m, 6H), 1.81(d, J=11.0 Hz, 2H), 1.54-1.40 (m, 2H) ppm; MS (ES) 594 (M+H).

(h) Synthetic Example: Carboxamide Compounds

Compounds were prepared as shown in Scheme 1(h).

Step 1

To a solution of 2-tert-butyl 8-methyl3,4-dihydro-1H-pyrido[4,3-b]indole-2,8(5H)-dicarboxylate (0.50 g, 1.5mmol) in DCM (5.0 mL), TFA (5.0 mL) was added. After allowing thereaction mixture to stir at room temperature for 1 h, the volatiles wereevaporated, DCM and toluene (20 mL) were added and the volatilesevaporated (2×). The resulting residue was dissolved in THF/MeOH (4:1,10 mL) and benzaldehyde (0.17 mL, 0.18 g, 1.7 mmol) and sodiumtriacetoxyborohydride (0.485 g, 2.3 mmol) were added. The reactionmixture was allowed to stir at room temperature overnight and 4 moreequivalents of the aldehyde and reducing agent were added to cause thereaction to go to completion. The reaction mixture was then poured intosaturated sodium bicarbonate solution (300 mL). The layers wereseparated, and the aqueous layer was extracted with DCM (3×100 mL). Thecombined organic layers were washed with brine (2×50 mL), dried (MgSO₄),filtered and concentrated to give a foamy residue. Column chromatography(DCM→3% MeOH/DCM) provided methyl2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate (12a inScheme 1(h)) as a white solid (0.32 g, 66%). ¹H NMR (CD₃OD, 300 MHz)8.17 (d, J=1.1 Hz, 1H), 7.73 (dd, J=8.7, 1.8 Hz, 1H), 7.44-7.27 (m, 6H),3.88 (s, 3H), 3.83 (s, 2H), 3.73 (s, 2H), 2.95-2.88 (m, 4H) ppm; MS (ES)321 (M+H).

Methyl2-(4-fluorobenzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate(12b in Scheme 1(h)) was prepared in similar fashion as a white solid(51%). ¹H NMR (CD₃OD, 300 MHz) 8.04 (d, J=1.4 Hz, 1H), 7.73 (dd, J=8.5,1.7 Hz, 1H), 7.46-7.41 (m, 2H), 7.30 (d, J=8.5 Hz, 1H), 7.09 (t, J=8.8Hz, 2H), 3.88 (s, 3H), 3.81 (s, 2H), 3.72 (s, 2H), 2.90 (br s, 4H) ppm;MS (ES) 339 (M+H).

Methyl2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate(12c in Scheme 1(h)) was prepared in similar fashion as an off-whitesolid (0.37 g, 63%). ¹H NMR (CD₃OD, 300 MHz) 8.05 (d, J=1.1 Hz, 1H),7.73 (dd, J=8.5, 1.7 Hz, 1H), 7.67 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.8 Hz,2H), 7.30 (d, J=8.5 Hz, 1H), 3.91 (s, 2H), 3.88 (s, 3H), 3.75 (s, 2H),2.91 (br s, 4H) ppm; MS (ES) 389 (M+H).

Step 2

To a solution of methyl2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate (12a,0.31 g, 1.0 mmol) in THF/MeOH (2:1, 9 mL), a solution of lithiumhydroxide hydrate (0.24 g, 5.7 mmol) in water (3.0 mL) was added. Afterallowing the reaction mixture to stir at room temperature for 2d, thevolatiles were evaporated to give a yellow residue. Trituration of theresidue with 10% HCl solution provided2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylic acid(13a in Scheme 1(h)) as a yellow solid (0.27 g, 92%). ¹H NMR (DMSO-d₆,300 MHZ) 11.59 (s, 1H), 10.92 (s, 1H), 8.07 (s, 1H), 7.71 (d, J=8.5 Hz,1H), 7.65 (d, J=3.6 Hz, 2H), 7.49 (d, J=3.6 Hz, 3H), 7.39 (d, J=8.5 Hz,1H), 4.58-4.30 (m, 4H), 3.78-3.69 (m, 1H), 3.52-3.05 (m, 3H) ppm; MS(ES) 307 (M+H).

2-(4-Fluorobenzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylicacid (13b in Scheme 1(h)) was prepared as a white solid from methyl2-(4-fluorobenzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate(12b) in similar fashion (99%). ¹H NMR (CD₃OD, 300 MHz) 8.16 (s, 1H),7.84 (dd, J=8.5, 1.7 Hz, 1H), 7.66-7.61 (m, 2H), 7.39 (d, J=8.5 Hz, 1H),7.28 (t, J=8.67 Hz, 2H), 4.58 (s, 2H), 4.53 (br s, 2H), 3.76 (br s, 2H),3.24 (t, J=5.8 Hz, 2H) ppm; MS (ES) 325 (M+H).

2-(4-(Trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylicacid (13c in Scheme 1(h)) was prepared as an off-white solid from methyl2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate(12c) in similar fashion (97%). ¹H NMR (CD₃OD, 300 MHz) 8.17 (s, 1H),7.88-7.79 (m, 5H), 7.39 (d, J=8.5 Hz, 1H), 4.69 (s, 2H), 4.62 (br s,1H), 4.54 (br s, 1H), 3.90 (br s, 1H), 3.66 (br s, 1H), 3.26 (br s, 2H)ppm; MS (ES) 375 (M+H).

Step 3

2-Benzyl-N-(1-(4-cyanobenzyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 4) was prepared as an off-white solid from2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylic acid(13a in Scheme 1(h)) as described in step 2 of Synthetic Example 1(b)above (97%). ¹H NMR (DMSO-d₆, 300 MHZ) 11.00 (s, 1H), 8.00 (d, J=7.7 Hz,1H), 7.82 (s, 1H), 7.78 (d, J=8.3 Hz, 2H), 7.53 (d, J=11.8 Hz, 1H), 7.50(d, J=7.7 Hz, 2H), 7.39 (d, J=6.6 Hz, 2H), 7.36 (d, J=8.3 Hz, 2H),7.32-7.23 (m, 2H), 3.76 (s, 3H), 3.58 (s, 2H), 3.56 (s, 2H), 2.89-2.73(m, 6H), 2.06 (t, J=11.0 Hz, 2H), 1.76 (d, J=9.9 Hz, 2H), 1.58 (q,J=10.7 Hz, 2H) ppm; MS (ES) 504 (M+H).

2-Benzyl-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 5) was prepared as an off-white solid from2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylic acid(13a) as described in step 2 of Synthetic Example 1(b) above (83%). ¹HNMR (DMSO-d₆, 300 MHZ) 11.01 (s, 1H), 8.01 (d, J=7.7 Hz, 1H), 7.82 (s,1H), 7.68 (d, J=8.0 Hz, 2H), 7.55-7.51 (m, 3H), 7.40-7.32 (m, 3H),7.28-7.23 (m, 3H), 3.76 (s, 3H), 3.59 (s, 2H), 3.56 (s, 2H), 2.90-2.72(m, 6H), 2.05 (t, J=11.3 Hz, 2H), 1.77 (d, J=9.9 Hz, 2H), 1.59 (q,J=10.5 Hz, 2H) ppm; MS (ES) 547 (M+H).

2-Benzyl-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 7) was prepared as a white solid upon HPLC purification from2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylic acid(13a) as a yellow solid as described in step 2 of Synthetic Example 1(b)above (43%). ¹H NMR (DMSO-d₆, 300 MHZ) 11.49 (s, 1H), 10.39 (br s, 1H),10.01 (br s, 1H), 8.69 (d, J=5.5 Hz, 2H), 8.30 (d, J=7.7 Hz, 1H), 7.93(s, 1H), 7.64-7.51 (m, 7H), 7.36 (d, J=8.5 Hz, 1H), 4.60-4.30 (m, 5H),4.00 (br s, 1H), 3.80-3.25 (m, 5H), 3.14 (br s, 4H), 2.04 (d, J=11.3 Hz,2H), 1.79 (q, J=11.6 Hz, 2H) ppm; MS (ES) 480 (M+H).

2-(4-Fluorobenzyl)-N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 8) was prepared as an off-white solid from2-(4-fluorobenzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylicacid (13b in Scheme 1(h)) as described in step 2 of Synthetic Example1(b) above (81%). ¹H NMR (CD₃OD, 300 MHz) 8.51 (br s, 1H), 8.44 (dd,J=4.8, 1.5 Hz, 1H), 7.87-7.82 (m, 2H), 7.55 (dd, J=8.4, 1.8 Hz, 1H),7.46-7.40 (m, 3H), 7.29 (d, J=8.5 Hz, 1H), 7.08 (t, J=8.8 Hz, 2H),3.96-3.84 (m, 1H), 3.80 (s, 2H), 3.71 (s, 2H), 3.61 (s, 2H), 2.98-2.86(m, 6H), 2.21 (t, J=11.1 Hz, 2H), 1.95 (d, J=11.3 Hz, 2H), 1.69 (qd,J=11.8, 3.0 Hz, 2H) ppm; MS (ES) 498 (M+H).

N-(1-(4-Cyanobenzyl)piperidin-4-yl)-2-(4-fluorobenzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 9) was prepared as an off-white solid from2-(4-fluorobenzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylicacid (13b) as described in step 2 of Synthetic Example 1(b) above (87%).¹H NMR (CD₃OD, 300 MHz) 7.84 (d, J=1.4 Hz, 1H), 7.69 (d, J=8.3 Hz, 2H),7.57-7.53 (m, 3H), 7.47-7.42 (m, 2H), 7.29 (d, J=8.5 Hz, 1H), 7.09 (t,J=8.8 Hz, 2H), 3.96-3.84 (m, 1H), 3.82 (s, 2H), 3.72 (s, 2H), 3.63 (s,2H), 3.00-2.86 (m, 6H), 2.20 (t, J=11.2 Hz, 2H), 1.94 (d, J=10.2 Hz,2H), 1.70 (q, J=11.0 Hz, 2H) ppm; MS (ES) 522 (M+H).

2-(4-Fluorobenzyl)-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 10) as an off-white solid was prepared from2-(4-fluorobenzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylicacid (13b) as described in step 2 of Synthetic Example 1(b) above (73%).¹H NMR (CD₃OD, 300 MHz) 7.84 (d, J=1.1 Hz, 1H), 7.63 (d, J=8.0 Hz, 2H),7.57-7.53 (m, 3H), 7.44 (dd, J=8.5, 5.5 Hz, 2H), 7.29 (d, J=8.5 Hz, 1H),7.08 (t, J=8.7 Hz, 2H), 3.96-3.84 (m, 1H), 3.81 (s, 2H), 3.72 (s, 2H),3.63 (s, 2H), 3.00-2.86 (m, 6H), 2.20 (t, J=10.7 Hz, 2H), 1.94 (d,J=10.7 Hz, 2H), 1.70 (qd, J=11.8, 2.8 Hz, 2H) ppm; MS (ES) 565 (M+H).

N-(1-(Pyridin-3-ylmethyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 11) was prepared as an off-white solid from2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylicacid (13c in Scheme 1(h)) as described in step 2 of Synthetic Example1(b) above (66%). ¹H NMR (CD₃OD, 300 MHz) 8.51 (d, J=1.7 Hz, 1H), 8.44(dd, J=4.8, 1.5 Hz, 1H), 7.86-7.82 (m, 2H), 7.64 (AB q, J=11.7, 8.9 Hz,4H), 7.55 (dd, J=8.5, 1.9 Hz, 1H), 7.42 (dd, J=7.7, 5.0 Hz, 1H), 7.29(d, J=8.5 Hz, 1H), 3.96-3.84 (m, 3H), 3.73 (s, 2H), 3.61 (s, 2H),2.98-2.88 (m, 6H), 2.21 (t, J=11.8 Hz, 2H), 1.94 (d, J=10.7 Hz, 2H),1.69 (qd, J=11.8, 2.9 Hz, 2H) ppm; MS (ES) 548 (M+H).

N-(1-(4-Cyanobenzyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 12) was prepared as an off-white solid from2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylicacid (13c) as described in step 2 of Synthetic Example 1(b) above (63%).¹H NMR (CD₃OD, 300 MHz) 7.84 (d, J=1.4 Hz, 1H), 7.71-7.61 (m, 6H),7.57-7.53 (m, 3H), 7.44 (d, J=8.5 Hz, 1H), 3.96-3.84 (m, 3H), 3.74 (s,2H), 3.62 (s, 2H), 3.00-2.86 (m, 6H), 2.20 (t, J=11.4 Hz, 2H), 1.93 (d,J=11.3 Hz, 2H), 1.69 (qd, J=11.8, 3.0 Hz, 2H) ppm; MS (ES) 572 (M+H).

2-(4-(Trifluoromethyl)benzyl)-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 13) was prepared as an off-white solid from2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylicacid (13c) as described in step 2 of Synthetic Example 1(b) above (55%).¹H NMR (CD₃OD, 300 MHz) 7.84 (d, J=1.1 Hz, 1H), 7.68-7.61 (m, 6H),7.57-7.53 (m, 3H), 7.29 (d, J=8.5 Hz, 1H), 3.96-3.84 (m, 3H), 3.73 (s,2H), 3.63 (s, 2H), 3.00-2.88 (m, 6H), 2.20 (t, J=11.9 Hz, 2H), 1.94 (d,J=12.1 Hz, 2H), 1.70 (qd, J=11.7, 2.8 Hz, 2H) ppm; MS (ES) 615 (M+H).

N-(1-Phenethylpiperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 14) was prepared as an off-white solid from2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylicacid (13c) as described in step 2 of Synthetic Example 1(b) above (41%).¹H NMR (CD₃OD, 300 MHz) 7.85 (d, J=1.1 Hz, 1H), 7.65 (AB q, J=11.3, 8.8Hz, 4H), 7.57 (dd, J=8.5, 1.7 Hz, 1H), 7.32-7.17 (m, 6H), 3.98-3.88 (m,3H), 3.74 (s, 2H), 3.11 (d, J=11.8 Hz, 2H), 3.00-2.90 (m, 4H), 2.87-2.82(m, 2H), 2.67-2.62 (m, 2H), 2.26 (t, J=11.8 Hz, 2H), 1.99 (d, J=10.5 Hz,2H), 1.72 (qd, J=11.8, 2.9 Hz, 2H) ppm; MS (ES) 561 (M+H).

N-(1-(4-Fluorophenyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 15) was prepared as its bistrifluoroacetate salt and purifiedby reverse phase HPLC as a white solid from2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylicacid (13c) as described in step 2 of Synthetic Example 1(b) above (27%).¹H NMR (CD₃OD, 300 MHz) 8.16 (s, 1H), 7.95 (s, 1H), 7.88-7.79 (m, 6H),7.67 (dd, J=8.5, 1.4 Hz, 1H), 7.39 (dd, J=8.7, 2.1 Hz, 2H), 7.25 (dd,J=9.1, 4.4 Hz, 2H), 7.10 (t, J=8.7 Hz, 2H), 4.69 (d, J=2.2 Hz, 3H), 4.57(br s, 1H), 4.53 (s, 2H), 4.18-4.06 (m, 1H), 3.68 (d, J=12.7 Hz, 2H),3.28-3.22 (m, 2H), 3.14 (t, J=11.4 Hz, 2H), 2.16 (d, J=10.5 Hz, 2H),1.93 (qd, J=12.0, 3.1 Hz, 2H) ppm; MS (ES) 551 (M+H).

(i) Synthetic Example:5-Methyl-N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyridor-4,3-blindole-8-carboxamide(Compound 18)

Compound 18 was prepared as shown in Scheme 1(i)

Step 1

A solution of 2-tert-butyl 8-methyl3,4-dihydro-1H-pyrido[4,3-b]indole-2,8(5H)-dicarboxylate (17 in Scheme1(i), 1.0 g, 3.0 mmol) in DMF (6.0 mL) was added to a cold solution (icebath) of NaH (60%, 121 mg, 3.0 mmol) in DMF (3 mL). After stirring at 0°C. under N₂ atmosphere for 30 min, iodomethane (210 μL, 471 mg, 3.3mmol) was added dropwise. The reaction mixture was then allowed to warmup to room temperature overnight, cooled down to 0° C. and poured intosaturated NH₄Cl solution (20 mL). The resulting brown precipitate wasfiltered, dried and chromatographed (neat DCM→2% MeOH/DCM) to provide,upon trituration with ethyl ether, 2-tert-butyl 8-methyl5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2,8(5H)-dicarboxylate (18 inScheme 1(i), 0.82 g, 79%). ¹H NMR (CD₃OD, 300 MHz) 8.13 (s, 1H), 7.82(dd, J=8.8, 1.7 Hz, 1H), 7.38 (d, J=8.5 Hz, 1H), 4.64 (br s, 2H), 3.90(s, 3H), 3.84 (t, J=5.6 Hz, 2H), 3.69 (s, 3H), 2.86 (t, J=5.6 Hz, 2H),1.52 (s, 9H) ppm; MS (ES) 345 (M+H).

Step 2

To a solution of 2-tert-butyl 8-methyl5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2,8(5H)-dicarboxylate (18 inScheme 1(i), 0.30 g, 0.9 mmol) in DCM (3.0 mL), TFA (3.0 mL) was added.After allowing the reaction mixture to stir at room temperature for 0.5h, the volatiles were evaporated, DCM (20 mL) and cold 1N NaOH solution(20 mL) were added. After 5 min, the organic layer was separated, washedthe aqueous layer with DCM (2×20 mL), and the combined organic layer waswashed with brine (1×25 mL), dried (MgSO₄), filtered and concentrated togive the free amine as a clear oil. Treatment of the free amine with4-(trifluoromethyl)benzaldehyde (290 μL, 370 mg, 2.1 mmol) and sodiumtriacetoxyborohydride (340 mg, 1.6 mmol) in DCM (3 mL) at roomtemperature overnight provided upon pouring the reaction mixture intosaturated NaHCO₃ solution, separating the organic layer, extracting theaqueous layer with DCM, drying (MgSO₄) and concentration a yellow oil.Column chromatography (neat DCM→2% MeOH/DCM) provided methyl5-methyl-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate(19 in scheme 1(i)) as a white solid (0.28 g, 78%). ¹H NMR (CD₃OD, 300MHz) 8.05 (d, J=1.1 Hz, 1H), 7.79 (dd, J=8.8, 1.7 Hz, 1H), 7.64 (AB q,J=14.3, 8.3 Hz, 4H), 7.35 (d, J=8.8 Hz, 1H), 3.89 (s, 2H), 3.88 (s, 3H),3.74 (s, 2H), 3.67 (s, 3H), 2.95-2.88 (m, 4H) ppm; MS (ES) 403 (M+H).

Step 3

To a solution of methyl5-methyl-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate(19 in Scheme 1(i), 0.27 g, 0.7 mmol) in THF/MeOH (2:1, 6 mL), asolution of lithium hydroxide hydrate (0.17 g, 4.1 mmol) in water (2.0mL) was added. After allowing the reaction mixture to stir at roomtemperature for 3 d, the volatiles were evaporated to give a yellowresidue. Trituration of the residue with 10% HCl solution provided5-methyl-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylicacid (20 in scheme 1(i)) as an off-white solid (0.21 g, 82%). ¹H NMR(CD₃OD, 300 MHz) 8.17 (d, J=1.1 Hz, 1H), 7.90 (dd, J=8.5, 1.7 Hz, 1H),7.83 (AB q, J=15.8, 8.4 Hz, 4H), 7.46 (d, J=8.8 Hz, 1H), 4.66 (s, 2H),4.55 (s, 2H), 3.82-3.78 (m, 2H), 3.76 (s, 3H), 3.26 (t, J=5.9 Hz, 2H)ppm; MS (ES) 389 (M+H).

Step 4

5-Methyl-N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 18 of Table 1) was prepared as its bistrifluoroacetate saltand purified by reverse phase HPLC as an off-white solid from5-methyl-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylicacid as described in step 2 of Synthetic Example 1(b) above (33%). ¹HNMR (DMSO-d₆, 300 MHZ) 10.54 (br s, 1H), 9.79 (br s, 1H), 8.69 (s, 1H),8.67 (d, J=4.7 Hz, 1H), 8.31 (d, J=7.4 Hz, 1H), 7.96 (d, J=11.6 Hz, 2H),7.90 (d, J=8.0 Hz, 2H), 7.81 (d, J=8.0 Hz, 2H), 7.69 (d, J=8.3 Hz, 1H),7.55 (d, J=4.7 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 4.70-4.55 (m, 3H),4.50-4.33 (m, 4H), 4.02 (br s, 1H), 3.86 (br s, 1H), 3.71 (s, 3H),3.60-3.37 (m, 2H), 3.35-3.05 (m, 4H), 2.05 (d, J=13.2, 2H), 1.77 (q,J=12.2 Hz, 2H) ppm; MS (ES) 562 (M+H).

N-(1-(4-Cyanobenzyl)piperidin-4-yl)-5-methyl-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 16 of Table 1) was prepared as an off-white solid from5-methyl-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylicacid as described in step 2 of Synthetic Example 1(b) above (70%). ¹HNMR (CD₃OD, 300 MHz) 7.86 (d, J=1.4 Hz, 1H), 7.70-7.60 (m, 7H), 7.54 (d,J=8.3 Hz, 2H), 7.35 (d, J=8.5 Hz, 1H), 3.96-3.84 (m, 3H), 3.74 (s, 2H),3.68 (s, 3H), 3.62 (s, 2H), 3.20-2.86 (m, 6H), 2.19 (t, J=12.0 Hz, 2H),1.93 (d, J=11.8 Hz, 2H), 1.69 (qd, J=12.0, 3.2 Hz, 2H) ppm; MS (ES) 586(M+H).

5-Methyl-2-(4-(trifluoromethyl)benzyl)-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 17 of Table 1) was prepared as an off-white solid from5-methyl-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylicacid as described in step 2 of Synthetic Example 1(b) above (68%). ¹HNMR (CD₃OD, 300 MHz) 7.86 (d, J=1.4 Hz, 1H), 7.68-7.61 (m, 7H), 7.54 (d,J=8.0 Hz, 2H), 7.35 (d, J=8.5 Hz, 1H), 3.96-3.84 (m, 3H), 3.74 (s, 2H),3.68 (s, 3H), 3.63 (s, 2H), 3.20-2.88 (m, 6H), 2.19 (t, J=11.0 Hz, 2H),1.94 (d, J=12.4 Hz, 2H), 1.70 (qd, J=12.1, 3.3 Hz, 2H) ppm; MS (ES) 629(M+H).

(j) Synthetic Example:5-Acetyl-N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamideBistrifluoroacetate (Compound 20)

Compound 20 was prepared as shown in Scheme 1(j).

To a solution ofN-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 11, 50 mg, 0.09 mmol) in DMF (1.0 mL), NaH (60%, 5 mg, 0.13mmol) was added at room temperature. The resulting brown reactionmixture was allowed to stir for 20 min, cooled down to −25° C. andacetyl chloride (7 μL, 7.7 mg, 0.1 mmol) was added. The reaction mixturewas then allowed to warm up to room temperature over 1 h and poured overice-cold saturated NaHCO₃ solution to give a brown precipitate which wascollected and purified by reverse phase HPLC. The purified material wastriturated with ethyl ether to provide5-acetyl-N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 20) as its bistrifluoroacetate salt as a white solid (31%). ¹HNMR (CD₃OD, 300 MHz) 8.73 (d, J=1.7 Hz, 1H), 8.70 (dd, J=5.1, 1.5 Hz,1H), 8.14 (d, J=8.8 Hz, 1H), 8.07 (dt, J=7.4, 1.7 Hz, 1H), 7.97 (s, 1H),7.87-7.79 (m, 5H), 7.61 (dd, J=8.0, 5.0 Hz, 1H), 4.69 (s, 2H), 4.53 (s,2H), 4.45 (s, 2H), 4.26-4.14 (m, 1H), 3.77 (br s, 2H), 3.64-3.52 (m,4H), 3.28-3.20 (m, 2H), 2.80 (s, 3H), 2.26 (d, J=14.4 Hz, 2H), 1.99 (brs, 2H) ppm; MS (ES) 590 (M+H).

(k) Synthetic Example:2-(4-Fluorophenyl)-N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 36)

Compound 36 was prepared as shown in Scheme 1(k).

Step 1

A solution of methyl 4-amino-3-iodobenzoate (0.5 g, 1.8 mmol),1-(4-fluorophenyl)piperidin-4-one (1.05 g, 5.4 mmol),1,4-diazabicyclo[2.2.2]octane (0.61 g, 5.4 mmol) and palladium (II)acetate (20 mg, 0.09 mmol) in DMF (10.0 mL) was degassed, filled withargon (3×) and allowed to stir at 110° C. for 3.5 h. The reactionmixture was allowed to cool to room temperature and partitioned betweenEtOAc (40 mL) and water (40 mL), and the aqueous layer was extractedwith EtOAc (2×20 mL). The combined organic layers were washed with water(2×20 mL), brine (1×20 mL), dried (MgSO₄), filtered and concentrated.Column chromatography (25% EtOAc/hexane) provided, upon trituration withethyl ether, methyl2-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate(23 in Scheme 1(k)) as a yellow solid (0.23 g, 39%). ¹H NMR (CDCl₃, 300MHZ) 8.17 (s, 1H), 7.77 (d, J=7.2 Hz, 1H), 7.23 (d, J=8.0 Hz, 3H), 7.09(t, J=8.1 Hz, 2H), 4.53 (s, 2H), 3.96 (s, 3H), 3.73 (t, J=5.6 Hz, 2H),3.12 (br s, 2H) ppm; MS (ES) 325 (M+H).

Step 2

To a solution of methyl2-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate(23, 0.22 g, 0.7 mmol) in THF/MeOH (2:1, 3.0 mL), a solution of lithiumhydroxide hydrate (3×0.17 g, 3×4.0 mmol) in water (1.0 mL) was added.After allowing the reaction mixture to stir at room temperature untilthe starting material is consumed, the volatiles were evaporated to givea yellow residue. Trituration of the residue with 10% HCl solutionprovided2-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylicacid (24 in Scheme 1(k)) as a yellow solid (0.21 g, 98%). ¹H NMR(DMSO-d₆, 300 MHZ) 11.41 (s, 1H), 8.16 (s, 1H), 7.69 (dd, J=8.4, 1.5 Hz,1H), 7.44 (br s, 2H), 7.37 (d, J=8.5, 1H), 7.23 (t, J=8.0 Hz, 2H), 4.59(s, 2H), 3.80 (s, 2H), 3.06 (s, 2H) ppm; MS (ES) 311 (M+H).

Step 3

To a solution of2-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylicacid (24, 50 mg, 0.16 mmol) in DMF (2.0 mL), HATU (75 mg, 0.2 mmol),1-(pyridin-3-ylmethyl)piperidin-4-amine dihydrochloride (48 mg, 0.16mmol) and triethylamine (150 μL, 110 mg, 1.1 mmol) were added. Theresulting reaction mixture was allowed to stir at room temperatureovernight, poured into saturated sodium bicarbonate solution (10 mL) togive a precipitate, filtered and dried under vacuum overnight.Trituration with ethyl ether provided2-(4-fluorophenyl)-N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 36) as a pale yellow solid (57 mg, 73%). ¹H NMR (DMSO-d₆, 300MHZ) 11.08 (s, 1H), 8.49 (d, J=1.4 Hz, 1H), 8.45 (dd, J=4.8, 1.5 Hz,1H), 8.03 (d, J=8.0 Hz, 1H), 8.02 (s, 1H), 7.70 (dt, J=7.7, 1.8 Hz, 1H),7.56 (dd, J=8.4, 1.5 Hz, 1H), 7.35 (dd, J=7.7, 4.7 Hz, 1H), 7.28 (d,J=8.3 Hz, 1H), 7.06 (d, J=5.0 Hz, 2H), 7.05 (d, J=3.3 Hz, 2H), 4.37 (s,2H), 3.87-3.72 (m, 1H), 3.63 (t, J=5.2 Hz, 2H), 3.52 (s, 2H), 2.92-2.78(m, 4H), 2.12-2.00 (m, 2H), 1.80 (d, J=10.5 Hz, 2H), 1.61 (qd, J=11.7,3.0 Hz, 2H) ppm; MS (ES) 484 (M+H).

N-(1-(4-Cyanobenzyl)piperidin-4-yl)-2-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 34) was prepared as a pale yellow solid as described in step 3of synthetic example 1(k) above (73%). ¹H NMR (DMSO-d₆, 300 MHZ) 11.07(s, 1H), 8.02 (s, 2H), 7.79 (d, J=8.0 Hz, 2H), 7.57 (d, J=8.5 Hz, 1H),7.51 (d, J=8.0 Hz, 2H), 7.28 (d, J=8.5 Hz, 1H), 7.07 (s, 2H), 7.05 (d,J=3.3 Hz, 2H), 4.38 (s, 2H), 3.88-3.72 (m, 1H), 3.63 (t, J=5.5 Hz, 2H),3.58 (s, 2H), 2.89 (br s, 2H), 2.82 (d, J=11.3 Hz, 2H), 2.09 (t, J=10.7Hz, 2H), 1.81 (d, J=12.3 Hz, 2H), 1.63 (q, J=10.0 Hz, 2H) ppm; MS (ES)508 (M+H).

2-(4-Fluorophenyl)-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 37) was prepared as a pale yellow solid as described in step 3of Synthetic Example 1(k) (36%). ¹H NMR (DMSO-d₆, 300 MHZ) 11.08 (s,1H), 8.04 (d, J=8.0 Hz, 1H), 8.03 (s, 1H), 7.69 (d, J=8.3 Hz, 2H), 7.58(d, J=1.7 Hz, 1H), 7.54 (d, J=8.8 Hz, 2H), 7.28 (d, J=8.5 Hz, 1H), 7.07(s, 2H), 7.05 (d, J=3.3 Hz, 2H), 4.37 (s, 2H), 3.88-3.74 (m, 1H), 3.63(t, J=5.2 Hz, 2H), 3.57 (s, 2H), 2.92-2.78 (m, 4H), 2.08 (t, J=10.9,2H), 1.80 (d, J=10.7 Hz, 2H), 1.62 (q, J=11.4 Hz, 2H) ppm; MS (ES) 551(M+H).

2-(4-Fluorophenyl)-N-(1-(4-fluorophenylsulfonyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 35) was prepared as an off-white solid as described in step 3of Synthetic Example 1(k) (75%). ¹H NMR (DMSO-d₆, 300 MHZ) 11.09 (s,1H), 8.09 (d, J=7.4 Hz, 1H), 7.99 (s, 1H), 7.82 (dd, J=8.7, 5.4 Hz, 2H),7.51 (q, J=8.7 Hz, 3H), 7.27 (d, J=8.5 Hz, 1H), 7.07 (s, 2H), 7.05 (d,J=1.9 Hz, 2H), 4.37 (s, 2H), 3.86-3.72 (m, 1H), 3.70-3.58 (m, 4H), 2.88(br s, 2H), 2.44 (t, J=10.2 Hz, 2H), 1.90 (d, J=9.9 Hz, 2H), 1.63 (q,J=11.3 Hz, 2H) ppm; MS (ES) 551 (M+H).

l) Synthetic Example:N-(1-(4-Fluorobenzoyl)piperidin-4-yl)-2-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 39)

Compound 39 was prepared as described in Scheme 1(l).

Step 1

tert-Butyl4-(2-(4-Fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate(Compound 38) was prepared as an off-white solid as described in step 3of Synthetic Example 1(k) above (1.42 g, 98%). ¹H NMR (DMSO-d₆, 300 MHZ)11.08 (s, 1H), 8.05 (d, J=7.7 Hz, 1H), 8.02 (s, 1H), 7.57 (dd, J=8.4,1.8 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 7.07 (s, 2H), 7.05 (d, J=3.6 Hz,2H), 4.38 (s, 2H), 4.00-3.90 (m, 3H), 3.63 (br s, 2H), 2.92-2.84 (m,4H), 1.80 (d, J=11.8 Hz, 2H), 1.52-1.44 (m, 2H), 1.42 (s, 9H) ppm; MS(ES) 515 (M+Na).

Step 2

A solution of tert-butyl4-(2-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate(Compound 38, 50 mg, 100 μmol) in 4 N HCl/dioxane (3.0 mL) was allowedto stir at room temperature for 2 h. The reaction mixture was thenconcentrated, MeOH (5.0 mL) was added and the volatiles were evaporated(2×). The resulting residue was dissolved in DMF (2.0 mL) and4-fluorobenzoyl chloride (15 μL, 20 mg, 130 μmol) and triethylamine (0.5mL, 0.36 g, 3.6 mmol) were added. The resulting reaction mixture wasallowed to stir at room temperature overnight, poured into saturatedsodium bicarbonate solution (20 mL) to give a yellow solid which wastriturated with ethyl ether and then purified by reverse phase HPLC toprovideN-(1-(4-fluorobenzoyl)piperidin-4-yl)-2-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 39) (46%). ¹H NMR (DMSO-d₆, 300 MHZ) 11.13 (s, 1H), 8.09 (d,J=7.7 Hz, 1H), 8.03 (s, 1H), 7.58 (dd, J=8.4, 1.5 Hz, 1H), 7.45 (dd,J=8.5, 5.5 Hz, 2H), 7.28 (t, J=8.8 Hz, 3H), 7.10 (m, 4H), 4.43 (s, 3H),4.18-4.03 (m, 2H), 3.70-3.54 (m, 3H), 3.16 (br s, 1H), 2.92 (br s, 2H),1.87 (br s, 2H), 1.54 (br s, 2H) ppm; MS (ES) 515 (M+H).

2-(4-Fluorophenyl)-N-(1-nicotinoylpiperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 40) was prepared as a yellow solid as described in step 2 ofSynthetic Example 1(l) above (22%). ¹H NMR (DMSO-d₆, 300 MHZ) 11.15 (s,1H), 8.69 (d, J=5.0 Hz, 1H), 8.65 (s, 1H), 8.12 (d, J=7.7 Hz, 1H), 8.04(s, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.56 (d, J=5.2Hz, 1H), 7.30 (d, J=8.5 Hz, 1H), 7.16-7.08 (m, 4H), 4.60-4.40 (m, 3H),4.11 (br s, 1H), 3.69 (br s, 2H), 3.63-3.51 (m, 1H), 3.30-3.18 (br s,1H), 3.06-2.88 (m, 3H), 2.00-1.77 (m, 2H), 1.69-1.42 (m, 2H) ppm; MS(ES) 498 (M+H).

2-(4-Fluorophenyl)-N-(1-(4-(trifluoromethyl)benzoyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 41) was prepared as a yellow solid as described in step 2 ofSynthetic Example 1(1) (35%). ¹H NMR (DMSO-d₆, 300 MHZ) 11.14 (s, 1H),8.12 (d, J=7.7 Hz, 1H), 8.03 (s, 1H), 7.83 (d, J=8.3 Hz, 2H), 7.61-7.57(m, 3H), 7.30 (d, J=8.5 Hz, 1H), 7.13-7.06 (m, 4H), 4.52-4.43 (m, 1H),4.42 (s, 2H), 4.20-4.04 (m, 1H), 3.67 (br s, 2H), 3.52 (d, J=12.1 Hz,1H), 3.21 (t, J=12.1 Hz, 1H), 2.92 (br s, 2H), 2.00-1.75 (m, 2H),1.69-1.41 (m, 2H) ppm; MS (ES) 565 (M+H).

(m) Synthetic Example:2-(4-Carbamovlbenzyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 44)

Compound 44 was prepared as shown in Scheme 1(m).

Step 1

i) A solution of benzyl8-(1-(tert-butoxycarbonyl)piperidin-4-ylcarbamoyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(8 in Scheme 1(m), 1.0 g, 1.9 mmol) and Pd/C (10% wt., 0.2 g) in MeOH(20 mL) was allowed to stir at room temperature overnight. The palladiumwas then removed by filtration and washed with MeOH; and the resultingclear solution was concentrated to give tert-butyl4-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylateas an-off white solid (0.745 g, 100%). MS (ES) 399 (M+H).

ii) To a solution of tert-butyl4-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate(0.745 g, 1.9 mmol) in DMF (10 mL), 4-bromomethylbenzamide (0.44 g, 2.1mmol) and TEA (1.2 mL, 0.857 g, 8.5 mmol) were added. The resulting darkyellow reaction mixture was allowed to stir at room temperature under N₂atmosphere overnight and then poured into saturated sodium bicarbonatesolution (100 mL). The resulting precipitate was collected and driedunder vacuum overnight to provide tert-butyl4-(2-(4-carbamoylbenzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate(28 in Scheme 1(m)) as a white solid (0.75 g, 75%). ¹H NMR (DMSO-d₆, 300MHZ) 10.80 (s, 1H), 7.86-7.79 (m, 4H), 7.55 (d, J=8.5 Hz, 1H), 7.45 (d,J=8.3 Hz, 3H), 7.26 (d, J=8.5 Hz, 2H), 4.00-3.88 (m, 3H), 3.82 (s, 2H),3.65 (s, 2H), 2.92-2.80 (m, 6H), 1.80 (d, J=9.9 Hz, 2H), 1.54-1.47 (m,2H), 1.43 (s, 9H) ppm; MS (ES) 532 (M+H).

Step 2

i) A solution of tert-butyl4-(2-(4-carbamoylbenzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate(28, 745 mg, 1.4 mmol) in 4 N HCl/dioxane (20.0 mL) was allowed to stirat room temperature for 2 h. The reaction mixture was then concentratedto give a tan solid which was triturated with ethyl ether to give2-(4-carbamoylbenzyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamideas an off-white solid (700 mg, 99%); MS (ES) 432 (M+H).

ii) To a solution of2-(4-carbamoylbenzyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(75 mg, 0.15 mmol) in DMF (1.0 mL), α-bromo-p-tolunitrile (32 mg, 0.16mmol) and triethylamine (75 μL, 54 mg, 0.54 mmol) were added. Theresulting reaction mixture was allowed to stir at room temperatureovernight, poured into saturated sodium bicarbonate solution (20 mL) togive a white solid which was collected and triturated with ethyl etherto give2-(4-carbamoylbenzyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 44) (55 mg, 68%). ¹H NMR (DMSO-d₆, 300 MHZ) 11.01 (s, 1H),8.00 (d, J=7.4 Hz, 1H), 7.93 (br s, 1H), 7.84 (d, J=8.3 Hz, 2H), 7.82(br s, 1H), 7.78 (d, J=8.3 Hz, 2H), 7.54 (dd, J=10.2, 1.4 Hz, 1H), 7.50(d, J=8.3 Hz, 2H), 7.45 (d, J=8.3 Hz, 2H), 7.31 (br s, 1H), 7.25 (d,J=8.3 Hz, 1H), 3.81 (s, 2H), 3.78-3.68 (m, 1H), 3.60 (s, 2H), 3.55 (s,2H), 2.88 (m, 6H), 2.05 (t, J=10.6 Hz, 2H), 1.76 (d, J=10.7 Hz, 2H),1.58 (q, J=10.5 Hz, 2H) ppm; MS (ES) 547 (M+H).

2-(4-Carbamoylbenzyl)-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 45) was prepared as described in step 2.ii of SyntheticExample 1(m) above (54%). ¹H NMR (DMSO-d₆, 300 MHZ) 11.01 (s, 1H), 8.49(dd, J=4.4, 1.4 Hz, 2H), 8.00 (d, J=8.0 Hz, 1H), 7.93 (br s, 1H), 7.84(d, J=8.3 Hz, 2H), 7.83 (br s, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.45 (d,J=8.0 Hz, 2H), 7.30 (d, J=5.8 Hz, 3H), 7.25 (d, J=8.5 Hz, 1H), 3.81 (s,2H), 3.78-3.70 (m, 1H), 3.60 (s, 2H), 3.50 (s, 2H), 2.88-2.76 (m, 6H),2.05 (t, J=11.0, 2H), 1.77 (d, J=11.3 Hz, 2H), 1.51 (q, J=11.8 Hz, 2H)ppm; MS (ES) 523 (M+H).

2-(4-Carbamoylbenzyl)-N-(1-isonicotinoylpiperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 46) was prepared as described in step 2.ii of SyntheticExample 1(m) above (31%). ¹H NMR (DMSO-d₆, 300 MHZ) 11.03 (s, 1H), 8.66(dd, J=4.4, 1.7 Hz, 2H), 8.07 (d, J=7.2 Hz, 1H), 7.93 (br s, 1H), 7.84(d, J=8.0 Hz, 2H), 7.82 (br s, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.45 (d,J=8.0 Hz, 2H), 7.35 (dd, J=4.4, 1.7 Hz, 2H), 7.32 (br s, 1H), 7.26 (d,J=8.5 Hz, 1H), 4.44 (d, J=12.9 Hz, 1H), 4.13-4.00 (m, 1H), 3.81 (s, 2H),3.59 (s, 2H), 3.45 (d, J=11.8 Hz, 1H), 3.17 (t, J=12.2 Hz, 1H), 2.94 (t,J=12.7 Hz, 1H), 2.84 (br s, 4H), 1.92 (d, J=11.0 Hz, 1H), 1.78 (d,J=11.0 Hz, 1H), 1.50 (q, J=12.8 Hz, 2H) ppm; MS (ES) 537 (M+H).

2-(4-Carbamoylbenzyl)-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 47) was prepared as described in step 2.ii of SyntheticExample 1(m) above (66%). ¹HNMR (DMSO-d₆, 300 MHZ) 11.01 (s, 1H), 8.00(d, J=7.4 Hz, 1H), 7.93 (br s, 1H), 7.84 (d, J=8.3 Hz, 2H), 7.83 (s,1H), 7.68 (d, J=8.0 Hz, 2H), 7.55-7.51 (m, 3H), 7.45 (d, J=8.3 Hz, 2H),7.31 (br s, 1H), 7.25 (d, J=8.3 Hz, 1H), 3.81 (s, 2H), 3.78-3.70 (m,1H), 3.60 (s, 2H), 3.56 (s, 2H), 2.88-2.74 (m, 6H), 2.05 (t, J=11.1 Hz,2H), 1.76 (d, J=10.2 Hz, 2H), 1.58 (q, J=10.7 Hz, 2H) ppm; MS (ES) 590(M+H).

2-(4-Carbamoylbenzyl)-N-(1-(4-fluorobenzyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 48) was prepared as described in step 2.ii of SyntheticExample 1(m) above (60%). ¹H NMR (DMSO-d₆, 300 MHZ) 11.01 (s, 1H), 8.00(d, J=7.7 Hz, 1H), 7.93 (br s, 1H), 7.84 (d, J=8.0 Hz, 2H), 7.82 (s,1H), 7.54 (d, J=8.5 Hz, 1H), 7.45 (d, J=8.0 Hz, 2H), 7.34-7.29 (m, 3H),7.25 (d, J=8.5 Hz, 1H), 7.13 (t, J=8.7 Hz, 2H), 3.81 (s, 2H), 3.78-3.68(m, 1H), 3.60 (s, 2H), 3.44 (s, 2H), 2.88-2.74 (m, 6H), 2.00 (t, J=11.0Hz, 2H), 1.75 (d, J=9.9 Hz, 2H), 1.56 (qd, J=11.8, 2.5 Hz, 2H) ppm; MS(ES) 539 (M+H).

2-(4-carbamoylbenzyl)-N-(1-(4-carbamoylbenzyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide(Compound 49) was prepared as described in step 2.ii of SyntheticExample 1(m) above (80%). ¹H NMR (DMSO-d₆, 300 MHZ) 11.01 (s, 1H), 7.99(d, J=7.4 Hz, 1H), 7.92 (d, J=5.8 Hz, 2H), 7.86-7.80 (m, 5H), 7.54 (d,J=8.5 Hz, 1H), 7.45 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 7.30 (d,J=3.3 Hz, 2H), 7.25 (d, J=8.5 Hz, 1H), 3.81 (s, 2H), 3.78-3.68 (m, 1H),3.60 (s, 2H), 3.50 (s, 2H), 2.88-2.76 (m, 6H), 2.02 (t, J=11.3 Hz, 2H),1.75 (d, J=10.7 Hz, 2H), 1.57 (q, J=10.64 Hz, 2H) ppm; MS (ES) 565(M+H).

(n). Increase in AMPK Activity

Compounds 1-54 were assayed for their ability to activate AMPK using anenzyme-linked immunosorbent assay. The EC₅₀ values for AMPK activationfor compounds 1-54 are presented in Table 2 below, in which “A” is lessthan 0.5 μM; “B” is 0.5-1 μM; “C” is 1-5 μM; and “D” is 5-10 μM; “E” is10-50 μM; and “F” is >100 μM:

TABLE 2 Cpd No. AMPK EC₅₀ 1 C 2 E 3 E 4 C 5 C 6 B 7 D 8 D 9 A 10 B 11 A12 A 13 A 14 A 15 A 16 A 17 B 18 C 19 F 20 C 21 B 22 B 23 C 24 C 25 E 26E 27 C 28 C 29 C 30 C 31 C 32 C 33 C 24 C 35 E 36 F 37 D 38 E 39 E 40 F41 E 43 F 44 E 45 F 46 F 47 E 48 F 49 F 50 A 51 B 52 C 53 E 54 A

Example 2 (a) Synthetic Example:4-((4-benzylpiperazin-1-yl)methyl)-N-(1-benzylpiperidin-4-yl)benzamide(compound 55)

Step 1

To a stirred mixture of 4-formylbenzoic acid (1 g, 6.66 mmol) inanhydrous dichloromethane (5 mL) was added triethylamine (1.4 mL, 7.99mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.53g, 7.99 mmol), and 1-benzyl-piperidin-4-ylamine (1.26 mL, 6.66 mmol).The mixture was stirred at room temperature overnight and thenconcentrated under reduced pressure. The residue obtained was trituratedwith methanol. The resulting solids were collected by filtration, washedmethanol and dried under reduced pressure to affordN-(1-benzylpiperidin-4-yl)-4-formylbenzamide as a white solid (1.7 g,80%). ¹H NMR (DMSO, 300 MHz): δ 8.41 (s, 1H), 7.85 (d, 2H), 7.77 (d,2H), 7.28 (m, 5H), 3.78 (m, 1H), 3.4 (m, 2H), 3.80 (m, 2H), 2.05 (m,2H), 1.45-1.80 (m, 4H); LCMS (m/z): 324 (MH⁺).

Step 2

N-(1-Benzylpiperidin-4-yl)-4-formylbenzamide (100 mg, 0.31 mmol) and1-benzylpipeazine (54 μL, 0.31 mmol) were mixed in 1,2 dichloroethane (5mL) and treated with sodium triacetoxyborohydride (86 mg, 0.403 mmol).The mixture was stirred at room temperature under N₂ overnight. Thereaction mixture was quenched with 1N NaOH, and the product wasextracted with EtOAc. The organic layers were washed with brine anddried (MgSO₄). The final product was purified by flash chromatography(2% MeOH/CH₂Cl₂) to afford the title compound as a white solid. (104 mg,70%) ¹H NMR (CDCl₃, 300 MHz): δ 7.89 (d, 2H), δ 7.46-7.62 (m, 5H), δ7.31-7.44 (m, 5H), δ 7.28 (d, 2H), δ 4.25 (s, 2H), δ 4.22 (s, 4H), δ3.98 (m, 2H), δ 3.44 (m, 8H), δ 2.88 (m, 2H), 62.56 (m, 2H), δ 2.45 (m,2H), δ 2.20 (m, 2H); LCMS (m/z): 484 (MH⁺).

(b) ¹H-NMR and Mass Spectral Data

The following compounds were prepared using methods analogous to thosedescribed in Synthetic Example 2(a) and in Scheme 2.

Compound 56:N-(1-benzylpiperidin-4-yl)-4-(4-(cyclohexylmethyl)piperazin-1-yl)methyl)benzamide.¹H NMR (CDCl₃, 300 MHz): δ 7.68 (d, 2H), 7.29-7.38 (m, 7H), 6.05 (d,1H), 4.02 (m, 1H), 3.61 (s, 2H), 3.57 (s, 2H), 2.97 (m, 2H), 2.28 (m,4H), 2.02 (m, 2H), 1.77-2.05 (m, 12H), 1.23 (m, 7H), 0.91 (m, 4H); LCMS(m/z): 490 (MH⁺).

Compound 57:N-(1-benzylpiperidin-4-yl)-4-((4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)benzamide.¹H NMR (CDCl₃, 300 MHz): δ 8.38 (s, 1H), 7.93 (d, 2H), 7.77 (d, 2H),7.26-7.46 (m, 5H), 6.62 (d, 1H), 4.44 (m, 1H), 4.25 (s, 2H), 4.20 (s,2H), 3.90 (m, 2H), 3.50 (m, 6H), 3.0 (m, 2H), 2.95 (m, 2H), 2.50 (m,2H), 2.21 (m, 2H); LCMS (m/z): 538 (MH⁺).

Compound 58:N-(1-benzylpiperidin-4-yl)-4-(4-(pyridin-2-yl)piperazin-1-yl)methyl)benzamide.¹H NMR (CDCl₃, 300 MHz): δ 8.36 (s, 1H), 7.78 (d, 1H), 7.43 (d, 2H),7.42-7.66 (m, 7H), 7.16 (d, 1H), 6.61 (d, 2H), 4.20 (m, 1H), 4.10 (s,2H), 3.65 (s, 2H), 3.65 (m, 4H), 3.42 (m, 2H), 2.70 (m, 6H), 2.20 (m,2H); LCMS (m/z): 470 (MH⁺).

Compound 59:4-((4-benzylpiperazin-1-yl)methyl)-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)benzamide.¹H NMR (CDCl₃, 300 MHz): δ 8.48 (d, 2H), δ 8.16 (d, 1H), δ 7.75 (d, 2H),67.28 (m, 9H), δ 3.75 (m, 1H), δ 3.47 (s, 2H), δ 3.43 (s, 2H), δ 3.31(s, 2H), δ 2.78 (m, 2H), δ 2.48 (s, 8H), δ 2.05 (m, 2H), δ 1.75 (m, 2H),δ 1.61 (m, 2H); LCMS (m/z): 484 (MH⁺).

Compound 60:4-((4-benzylpiperazin-1-yl)methyl)-N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)benzamide.¹H NMR (CDCl₃, 300 MHz): δ 8.43 (m, 3H), δ 8.14 (d, 2H), δ 7.73 (d, 2H),67.66 (d, 2H), 67.31 (m, 7H), δ 3.74 (m, 1H), δ 3.47 (s, 2H), δ 3.43 (s,2H), δ 3.31 (s, 2H), δ 2.81 (m, 2H), δ 2.48 (s, 8H), δ 2.11 (m, 2H), δ1.65 (m, 2H), δ 1.55 (m, 2H); LCMS (m/z): 484 (MH⁺).

Compound 61:4-((4-benzylpiperazin-1-yl)methyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)benzamide.¹H NMR (CDCl₃, 300 MHz): δ 8.25 (d, 2H), δ 7.76 (m, 4H), δ 7.48 (d, 2H),δ7.28 (m, 5H), δ 3.74 (m, 1H), δ 3.55 (s, 2H), δ 3.48 (d, 2H), δ 3.31(s, 2H), δ 2.78 (m, 2H), δ 2.48 (s, 8H), δ 2.08 (m, 2H), δ 1.75 (m, 2H),δ 1.58 (m, 2H); LCMS (m/z): 508 (MH⁺).

Compound 62:4-((4-benzylpiperazin-1-yl)methyl)-N-(1-(4-trifluoromethylbenzyl)piperidin-4-yl)benzamide.¹H NMR (CDCl₃, 300 MHz): δ 8.18 (d, 1H), δ 7.73 (d, 2H), δ 7.67 (d, 2H),δ 7.51 (d, 2H), δ 7.32 (d, 2H), 67.26 (m, 5H), δ 3.74 (m, 1H), δ 3.55(s, 2H), δ 3.45 (d, 2H), δ 3.31 (s, 2H), δ 2.68 (m, 2H), δ 2.48 (s, 8H),δ 2.05 (m, 2H), δ 1.75 (m, 2H), δ 1.58 (m, 2H); LCMS (m/z): 551 (MH⁺).

(c) Increase in AMPK Activity

Compounds 55-62 of Table 1 were assayed for their ability to activateAMPK using an enzyme-linked immunosorbent assay. The EC₅₀ values forAMPK activation for compounds 55-62 are presented in Table 3 below, inwhich “A” is less than 0.1 μM; “B” is 0.1-0.5 μM; “C” is 0.5-1 μM; and“D” is 1-10 μM; “E” is 10-100 μM; and “F” is >100 μM:

TABLE 3 Cpd No. AMPK EC₅₀ 55 A 56 D 57 A 58 D 59 B 60 B 61 A 62 A

Example 3 (a) Synthetic Example:N-(1-benzylpiperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)-2-naphthamide(Compound 65)

Step 1

To a stirred mixture of 6-hydroxy-2-napthoic acid (100 mg, 0.531 mmol)in anhydrous dimethylormamide (5 mL) was added triethylamine (163 μl,1.168 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(112 mg, 0.584 mmol), and 1-benzyl-piperidine-4-amine (100 μl, 0.531mmol). The mixture was allowed to stir at room temperature overnight,then poured into water. The resulting solids were collected byfiltration and purified by column chromatography to yieldN-(1-benzylpiperidin-4-yl)-6-hydroxy-2-naphthamide as a light brownsolid (0.191 g, 80%).

Step 2

To a stirred suspension ofN-(1-benzylpiperidin-4-yl)-6-hydroxy-2-naphthamide (0.1 g, 0.277 mmol)in toluene (5 mL) at room temperature was added diisopropylazodicarboxylate (82 μl, 0.416 mmol),1-(4-(trifluoromethyl)phenyl)piperidin-4-ol (0.068 g, 0.277 mmol), andtriphenyl phosphine (0.109 g, 0416 mmol). The mixture was stirred at 50°C. overnight, then concentrated under reduced pressure. The residue waspurified by flash chromatography (silica gel, 3% methanol in methylenechloride) to afford the title compound as a white solid (0.093 g, 57%).¹H-NMR (CDCl₃, 300 MHz): δ 8.738 (s, 1H), 8.242 (s, 1H), 8.093 (s, 1H),7.837-7.250 (m, 11H), 7.167 (s, 1H), 6.87 (m, 1H), 4.63 (m, 1H), 4.31(m, 1H), 4.162 (s, 2H), 3.647 (m, 2H), 3.557 (m, 2H), 3.519 (m, 2H),2.814 (m, 2H), 2.584 (m, 2H), 2.222-2.083 (m, 6H); LCMS: >98%; MS:588.28 (M+1).

(b) Increase in AMPK Activity

Compounds 63-66 of Table 1 were assayed for their ability to activateAMPK using an enzyme-linked immunosorbent assay. The EC₅₀ values forAMPK activation for compounds 63-66 are presented in Table 4 below, inwhich “A” is less than 0.5 μM; “B” is 0.5-1 μM; “C” is 1-5 μM; and “D”is 5-50 μM:

TABLE 4 Cpd No. AMPK EC₅₀ 63 A 64 A 65 C 66 C

Example 4 (a) Synthetic Example:N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)quinoline-3-carboxamide(Compound 69)

Step 1

6-Methoxyquinoline-3-carboxylic acid (2.5 g, 12.3 mmol) was suspended inanhydrous dichloromethane (20 mL) under nitrogen; the suspension wascooled to −78° C. A solution of BBr₃ in dichloromethane (100 mL of 1Msolution, 100 mmol) was added dropwise. The mixture was stirred for 30min at −78° C., warmed slowly to RT, and allowed to stir at roomtemperature overnight. The reaction was quenched by dropwise addition ofice-water. The resulting solids were collected by filtration, and washedwith water to yield 3.2 g (97%) of 6-hydroxyquinoline-3-carboxylic acidas an HBr salt. LCMS: >98%; MS: 190.27 (M+1, free base).

Step 2

To a stirred mixture of the product of step a (500 mg, 2.63 mmol) inanhydrous dimethylormamide (5 mL) was added triethylamine (733 μL, 5.62mmol), HATU (1.1 g, 2.89 mmol), and tert-butyl4-aminopiperidine-1-carboxylate (526 mg, 2.63 mmol). The mixture wasallowed to stir at room temperature overnight and then poured intowater. The resulting solids were collected by filtration and purified bycolumn chromatography to yield tert-butyl4-(6-hydroxyquinoline-3-carboxamido)piperidine-1-carboxylate as a lightbrown solid (0.7 g, 71%). LCMS (m/z): 372 (MH⁺)

Step 3

To a stirred suspension of the product of step 2 above (0.7 g, 1.88mmol) in toluene (15 mL) at room temperature was added diisopropylazodicarboxylate (557 μl, 2.83 mmol),1-(4-(trifluoromethyl)phenyl)piperidin-4-ol (0.693 g, 2.83 mmol), andtriphenyl phosphine (0.742 g, 2.83 mmol). The mixture was stirred at 50°C. overnight and then concentrated under reduced pressure. The residuewas purified by flash chromatography (silica gel, 3% methanol inmethylene chloride) to afford tert-butyl4-(6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)quinoline-3-carboxamido)piperidine-1-carboxylateas a white solid (0.306 g, 27%). LCMS (m/z): 599 (MH⁺)

Step 4

The product of step 3 above was dissolved in 4N HCl in dioxane, andstirred for 1 h at room temperature. The reaction mixture wasconcentrated to dryness. The residue (100 mg, 0.31 mmol) and4-cyanobenzaldehyde (33 mg, 0.247 mmol) were mixed in 1,2 dichloroethane(5 mL) and treated with sodium triacetoxyborohydride (70 mg, 0.328mmol). The mixture was stirred at room temperature under N₂ overnight,then quenched with 1N NaOH, and the product was extracted with EtOAc.The organic layers were washed with brine and dried (MgSO₄). The finalproduct was purified by flash chromatograph (2% MeOH/DCM) to afford thetitle compound as a white solid (87%). ¹H-NMR (CDCl₃, 300 MHz): δ 9.1(s, 1H), 8.468 (s, 1H), 8.015 (d, 2H), 7.689 (m, 4H), 7.467 (m, 4H),7.178 (s, 1H), 6.965 (d, 2H), 4.691 (s, 2H), 4.295 (m, 1H), 3.910 (m,1H), 3.628 (m, 2H), 3.336 (m, 4H), 2.592 (m, 2H), 2.174-2.053 (m, 8H);LCMS (m/z): 614 (MH⁺).

(b) Increase in AMPK Activity

Compounds 67-71 of Table 1 were assayed for their ability to activateAMPK using an enzyme-linked immunosorbent assay. The EC₅₀ values forAMPK activation for compounds 67-71 are presented in Table 5 below, inwhich “A” is less than 0.1 μM; “B” is 0.1-0.5 μM; “C” is 0.5-5 μM; and“D” is >5 μM:

TABLE 5 Cpd No. AMPK EC₅₀ 67 B 68 D 69 A 70 A 71 A

Example 5 (a) Synthetic Example:N-(1-benzylpiperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)-1H-indole-2-carboxamide(Compound 72)

Step 1

To a stirred mixture of 5-hydroxy-1H-indole-2-carboxylic acid (1.85 g,10.43 mmol) in anhydrous dimethylformamide (15 mL) was addedtriethylamine (1.73 mL), 1-hydroxybenzotriazole (1.64 g),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.39 g) and1-benzylpiperidin-4-ylamine (2.39 g, 12.54 mmol). The reaction mixturewas stirred at room temperature over-night and then solvents wereremoved under reduced pressure, poured into water, filter the solid andwashed with water. The solid was purified by silica gel columnchromatography, eluted with CH₂Cl₂:MeOH (93:7) to afford 0.87 g (24%) ofN-(1-benzylpiperidin-4-yl)-5-hydroxy-1H-indole-2-carboxamide as a whitesolid. ¹H NMR (DMSO-d₆, 300 MHz): δ 11.17 (s, 1H), 8.72 (s, 1H), 8.07(d, J=7.8 Hz, 1H), 7.7.29 (m, 6H), 6.91 (s, 1H), 6.82 (s, 1H), 6.68 (m,1H), 3.75 (br s, 1H), 3.46 (s, 2H), 2.81 (d, J=11.4 Hz, 2H), 2.02 (t,J=10.8 Hz, 2H), 1.77 (m, 2H), 1.56 (m, 2H); LCMS (m/z): 350 (MH⁺).

Step 2

To a stirred mixture ofN-(1-benzylpiperidin-4-yl)-5-hydroxy-1H-indole-2-carboxamide (85.5 mg,0.245 mmol) in anhydrous toluene (3 mL) at room temperature was addeddiisopropyl azodicarboxylate (0.05 mL, 0.25 mmol),1-(4-trifluorophenyl)piperidin-4-ol (60 mg, 0.245 mmol) andtriphenylphosphine (64 mg, 0.25 mmol). The reaction mixture was heatedwith stirred at 80° C. under N₂ atmosphere over-night and thenconcentrated under reduced pressure. The residue thus obtained waspurified by silica gel column chromatography, eluted with CH₂Cl₂:MeOH(97:3) and finally by HPLC to affordN-(1-benzylpiperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)-1H-indole-2-carboxamide(10 mg) as a white solid. LCMS (m/z): 577 (MH⁺).

(b) Increase in AMPK Activity

Compound 72 of Table 1 was assayed for its ability to activate AMPKusing an enzyme-linked immunosorbent assay. The EC₅₀ values for AMPKactivation for compound 72 is presented in Table 6 below, in which “A”is less than 0.1 μM; “B” is 0.1-0.5 μM; “C” is 0.5-1 μM; and “D” is 1-50μM:

TABLE 6 Cpd No. AMPK EC₅₀ 72 A

1. A compound having the structural formula

or a pharmaceutically acceptable salt, prodrug or N-oxide thereof,wherein “B” represents -(aryl or heteroaryl)- substituted by w R³ and kR¹⁴; the dotted line denoted by “a” is a bond or absent; D is a carbonor N when the dotted line denoted by “a” is absent, and a carbon whenthe dotted line denoted by “a” is a bond; J is —O—, —N(R³⁸)—, —CH₂—,—CH(R²⁶)— or —C(R²⁶)₂—; E is —C(O)—, —S(O)₂— or a single bond, providedthat when “B” is phenyl, J is —O— and D is a carbon, E is not —C(O)—; R¹is H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) or —C(O)O—(C₁-C₄ alkyl); R² is-Hca, -Cak-N(R⁹)-G-R²² or —(C₂-C₈ alkyl)-N(R⁹)—R²⁴ in which one or twocarbons of the (C₂-C₈ alkyl) are optionally replaced by —O—, —S— or—N(R⁹)— and R²⁴ is —R²³, -G-R²³, or —C(O)O—(C₁-C₆ alkyl), provided thattwo consecutive carbons of the (C₂-C₈ alkyl) are not replaced by —O—;each R³ is substituted on a benzo, pyrido or pyrazino carbon of the ringsystem denoted by “B” and is independently selected from —(C₁-C₆ alkyl),—(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN; w is 0, 1, 2 or 3; each R¹⁴is substituted on a non-benzo, non-pyrido, non-pyrazino carbon of thering system denoted by “B”, and is independently selected from —(C₁-C₆alkyl), —(C₁-C₆ halooalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het,—(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN; k is 0, 1 or 2; each R⁴ isindependently selected from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca,—(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, andtwo R⁴ on the same carbon optionally combine to form oxo; x is 0, 1, 2,3 or 4; p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4; the sum of p and qis 1, 2, 3 or 4; T is —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰ or

in which Q is —S(O)₂— L or —(C₀-C₃ alkyl)-, in which each carbon of the—(C₀-C₃ alkyl)- is optionally and independently substituted with one ortwo R¹⁶; the ring system denoted by “A” is heteroaryl, aryl, cycloalkylor heterocycloalkyl; each R⁵ is independently selected from —(C₁-C₆alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het,—(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆alkyl)-S(O)₀₋₂R¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, -halogen, —NO₂ and —CN; and yis 0, 1, 2, 3 or 4; in which each L is independently selected from—NR⁹C(O)O—, —OC(O)NR⁹—, —NR⁹C(O)—NR⁹—, —NR⁹C(O)S—, —SC(O)NR⁹—,—NR⁹C(O)—, —C(O)—NR⁹—, —NR⁹C(S)O—, —OC(S)NR⁹—, —NR⁹C(S)—NR⁹—,—NR⁹C(S)S—, —SC(S)NR⁹—, —NR⁹C(S)—, —C(S)NR⁹—, —SC(O)NR⁹—, —NR⁹C(S)—,—S(O)₀₋₂—, —C(O)O, —OC(O)—, —C(S)O—, —OC(S)—, —C(O)S—, —SC(O)—, —C(S)S—,—SC(S)—, —OC(O)O—, —SC(O)O—, —OC(O)S—, —SC(S)O—, —OC(S)S—,—NR⁹C(NR²)NR⁹—, —NR⁹SO₂—, —SO₂NR⁹— and —NR⁹SO₂NR⁹—, each R⁶, R⁷, R⁸ andR¹⁰ is independently selected from H, —(C₁-C₆ alkyl), —(C₁-C₆haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆ alkyl)-Cak,—(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆alkyl)-NR⁹—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆alkyl)-C(O)—(C₀-C₆ alkyl) and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), eachR⁹ is independently selected from —H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄alkyl) and —C(O)O—(C₁-C₄ alkyl), each G is independently —S(O)₂—, L or—(C₀-C₃ alkyl)-, in which each carbon of the —(C₀-C₃ alkyl)- isoptionally and independently substituted with one or two R¹⁶, each R¹⁶is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl),—(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰,-halogen, —NO₂ and —CN, and optionally two of R¹⁶ on the same carboncombine to form oxo, each R²⁶ is independently selected from —(C₁-C₆alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het,—(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, and optionally two of R²⁶ onthe same carbon combine to form oxo, each R³⁸ is independently selectedfrom —H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) and —C(O)O—(C₁-C₄ alkyl),each R²² and R²³ is independently Ar or Het, each Ar is an optionallysubstituted aryl, each Het is an optionally substituted heteroaryl, eachCak is an optionally substituted cycloalkyl, each Hca is an optionallysubstituted heterocycloalkyl, and each alkyl is optionally substituted.2. A compound according to claim 1, wherein “B” represents

the dotted line denoted by “a” is absent, k is 0, J is —N(R³⁸)— and D isa carbon.
 3. A compound according to claim 1, wherein the “B” represents

in which X¹ and X² are independently a carbon or N, and k is
 0. 4. Acompound according to claim 4, wherein one of X¹ and X² is a carbon andthe other is N.
 5. A compound according to claim 1, wherein “B”represents

in which R³⁹ is H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) or —C(O)O—(C₁-C₄alkyl).
 6. A compound according to claim 1, wherein E is —C(O)—.
 7. Acompound according to claim 1, wherein T is


8. A compound according to claim 7, wherein each R¹⁶ is independentlyselected from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-L-R⁷,—(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰,—(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, and two R¹⁶ on thesame carbon optionally combine to form an oxo, in which each R⁷, R⁸ andR¹⁰ is independently selected from H, —(C₁-C₆ alkyl), —(C₁-C₆haloalkyl), —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆alkyl), and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), and in which no alkylor haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group.
 9. A compound according to claim 7,wherein Q is —CH₂—, a single bond, —C(O)—, —S(O)₂— or —CH(CH₃)—.
 10. Acompound according to claim 7, wherein each R⁵ is independently selectedfrom —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰is independently selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl),—(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl) and —(C₀-C₆alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group.
 11. A compound according to claim 7,wherein the ring system denoted by “A” is an aryl or a heteroaryl.
 12. Acompound according to claim 7, wherein the ring system denoted by “A” isa phenyl.
 13. A compound according to claim 1, wherein the sum of p andq is 2 or
 3. 14. A compound according to claim 1, wherein R¹ is H.
 15. Acompound according to claim 1, wherein R² is Hca.
 16. A compoundaccording to claim 15, wherein R² is an optionally-substitutedmonocyclic heterocycloalkyl.
 17. A compound according to claim 15,wherein R² is -(optionally-substituted azetidin-3-yl), -(optionallysubstituted piperidin-4-yl), -(optionally substituted pyrrolidin-3-yl)or -(optionally-substituted azepan-4-yl).
 18. A compound according toclaim 17, wherein R² is substituted at its 1-position with —(C₀-C₃alkyl)-Ar or —(C₀-C₃ alkyl)-Het.
 19. A compound according to claim 17,wherein R² is substituted at its 1-position with —C(O)—O(C₀-C₆ alkyl),—C(O)—Het, —C(O)—Ar, —S(O)₂-Het, —S(O)₂—Ar or —S(O)₂—O(C₀-C₆ alkyl). 20.A compound according to claim 17, wherein R² is substituted at its1-position with —C(O)—NR⁹—Het or —C(O)—NR⁹—Ar.
 21. A compound accordingto claim 1 wherein R² is -Cak-N(R⁹)-G-R²².
 22. A compound according toclaim 1, wherein R² is —(C₂-C₈ alkyl)-N(R⁹)—R²⁴ in which one or twocarbons of the (C₂-C₈ alkyl) are optionally replaced by —O— or —N(R⁹)—and R²⁴ is —R²³, -GR²³, or —C(O)O—(C₁-C₆ alkyl).
 23. A compoundaccording to claim 1, wherein each R³ is independently selected from—(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰is independently selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl),—(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl), and —(C₀-C₆alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group.
 24. A compound according to claim 1,wherein each R⁴ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆haloalkyl), —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰,-halogen, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰ is independentlyselected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl) and —(C₀-C₆alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group.
 25. A compound according to claim 1,having the structural formula

in which Q and G are each independently a bond, —CH₂—, —C(H)(R¹⁶)—,—C(R¹⁶)₂—, L or —S(O)₂—; v is 0, 1, 2, 3 or 4; each R¹⁵ is independentlyselected from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar,—(C₀-C₆ alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, andtwo R¹⁵ on the same carbon optionally combine to form oxo; R¹⁷ is Het orAr.
 26. A compound according to claim 25, having the structural formula

in which R²⁷ is selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl),—(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl)-(C₀-C₆alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), in which no heterocycloalkyl, alkyl orhaloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group, and R²⁹ is —H, —(C₁-C₄ alkyl),—C(O)—(C₁-C₄ alkyl) or —CO—O—(C₁-C₄ alkyl) in which no (C₁-C₄ alkyl) issubstituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group, or R²⁷ and R²⁹ together with thenitrogen to which they are bound form Hca.
 27. A compound according toclaim 25, having the structural formula

in which R²⁷ is selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl),—(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl)-(C₀-C₆alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), in which no heterocycloalkyl, alkyl orhaloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group, and R²⁹ is —H, —(C₁-C₄ alkyl),—CO—O—(C₁-C₄ alkyl) or —CO—O—(C₁-C₄ alkyl) in which no (C₁-C₄ alkyl) issubstituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group, or R²⁷ and R²⁹ together with thenitrogen to which they are bound form Hca.
 28. A compound according toclaim 25, having the structural formula


29. A compound according to claim 25, having the structural formula

in which R²⁵ is selected from halo, cyano, —(C₁-C₄ haloalkyl), —O—(C₁-C₄haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl), —C(O)—(C₀-C₄ alkyl),—C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), NO₂ and—C(O)—Hca in which the Hca contains a ring nitrogen atom through whichit is bound to the —C(O)—, in which no alkyl or haloalkyl is substitutedby an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group.30. A compound according to claim 25, having the structural formula

in which Q is —C(O)—, —S(O)₂— or —C(O)—NH—.
 31. A compound according toclaim 25, wherein the

moiety has the structure

in which G is —CH₂—, —CH(CH₃)—, —C(O)—, —S(O)₂— or —C(O)—NH—.
 32. Acompound according to claim 25, wherein the

moiety has the structure

in which G is —CH₂—, —C(O)—, —S(O)₂— or —C(O)—NH—.
 33. A compoundaccording to claim 1, wherein the compound is4-((4-benzylpiperazin-1-yl)methyl)-N-(1-benzylpiperidin-4-yl)benzamideN-(1-benzylpiperidin-4-yl)-4-((4-(cyclohexylmethyl)piperazin-1-yl)methyl)benzamide;N-(1-benzylpiperidin-4-yl)-4-((4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)benzamide;N-(1-benzylpiperidin-4-yl)-4((4-(pyridin-2-yl)piperazin-1-yl)methyl)benzamide4-((4-benzylpiperazin-1-yl)methyl)-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)benzamide;4-((4-benzylpiperazin-1-yl)methyl)-N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)benzamide;4-((4-benzylpiperazin-1-yl)methyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)benzamide4-((4-benzylpiperazin-1-yl)methyl)-N-(1-(4-trifluoromethylbenzyl)piperidin-4-yl)benzamide;N-(1-benzylpiperidin-4-yl)-6-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yloxy)-2-naphthamide;N-(1-benzylpiperidin-4-yl)-6-(1-(4-cyanobenzyl)piperidin-4-yloxy)-2-naphthamideN-(1-benzylpiperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)-2-naphthamide;tert-butyl4-(7-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)-2-naphthamido)piperidine-1-carboxylate;tert-butyl4-(6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)quinoline-3-carboxamido)piperidine-1-carboxylate;N-(piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)quinoline-3-carboxamide;N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)quinoline-3-carboxamide;N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)quinoline-3-carboxamide;N-(1-benzylpiperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)quinoline-3-carboxamide;orN-(1-benzylpiperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)-1H-indole-2-carboxamide.34. A pharmaceutical composition comprising: at least onepharmaceutically acceptable carrier, diluent or excipient; and acompound according to claim 1 or a pharmaceutically acceptable salt,prodrug or N-oxide thereof.
 35. A method for activating the AMPK pathwayin a cell, the method comprising contacting the cell with an effectiveamount of a compound according to claim 1, or a pharmaceuticallyacceptable salt, prodrug or N-oxide thereof.
 36. A method for increasingfatty acid oxidation in a cell, the method comprising contacting thecell with an effective amount of a compound according to claim 1, or apharmaceutically acceptable salt, prodrug or N-oxide thereof.
 37. Amethod for decreasing glycogen concentration in a cell, the methodcomprising contacting the cell with an effective amount of a compoundaccording to claim 1, or a pharmaceutically acceptable salt, prodrug orN-oxide thereof.
 38. A method for increasing glucose uptake in a cell,the method comprising contacting the cell with an effective amount of acompound according to claim 1, or a pharmaceutically acceptable salt,prodrug or N-oxide thereof.
 39. A method for reducing triglyceridelevels in a subject, the method comprising administering to the subjectan effective amount of a compound according to claim 1, or apharmaceutically acceptable salt, prodrug or N-oxide thereof.
 40. Amethod for treating type II diabetes in a subject, the method comprisingadministering to the subject an effective amount of a compound accordingto claim 1, or a pharmaceutically acceptable salt, prodrug or N-oxidethereof.
 41. A method for treating or preventing atherosclerosis orcardiovascular disease in a subject, the method comprising administeringto the subject an effective amount of a compound according to claim 1,or a pharmaceutically acceptable salt, prodrug or N-oxide thereof.
 42. Alabeled conjugate having the structural formula

in which the “LINK” moiety is a linker and is optional, and the “LABEL”moiety is a labeling agent, and the

moiety is as described in claim 1.